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2008-01-12T06:10:00.000-08:00

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hypermagnesemia

2007-12-14T19:01:00.000-08:00

Introdution
Hypermagnesemia is an uncommon clinical finding, and symptomatic hypermagnesemia is even less common. This disorder has a low incidence of occurrence, because the kidney is able to eliminate excess magnesium by rapidly reducing its tubular reabsorption to almost negligible amounts.

In healthy adults, plasma magnesium ranges from 1.7-2.3 mg/dL. Approximately 30% of total plasma magnesium is protein-bound and approximately 70% is filterable through artificial membranes (15% complexed, 55% free Mg2+ ions). With a glomerular filtration rate (GFR) of approximately 150 L/d and an ultrafiltrable magnesium concentration of 14 mg/L, the filtered magnesium load is approximately 2,100 mg/d. Normally, only 3% of filtered magnesium appears in urine; thus, 97% is reabsorbed by the renal tubules. In contrast to sodium and calcium, only approximately 25-30% of filtered magnesium is reabsorbed in the proximal tubule. Approximately 60-65% of filtered magnesium is reabsorbed in the thick ascending loop of Henle and 5% is reabsorbed in the distal nephron. Relatively little is known about cellular magnesium transport mechanisms.

The most common cause of hypermagnesemia is renal failure. Other causes include the following:

Excessive intake

Lithium therapy

Hypothyroidism

Addison disease

Familial hypocalciuric hypercalcemia

Milk alkali syndrome

Depression
RENAL FAILURE Section 3 of 8
Author Information Introduction Renal Failure Other Causes Effects Of Hypermagnesemia Treatment Of Hypermagnesemia Acknowledgments Bibliography

Patients with end-stage renal disease often have mild hypermagnesemia, and the ingestion of magnesium-containing medications (eg, antacids, cathartics) can exacerbate the condition. In patients undergoing regular dialysis, the serum magnesium level directly relates to the dialysate-magnesium concentration.

In patients with acute renal failure, hypermagnesemia usually presents during the oliguric phase; the serum magnesium level returns to normal during the diuretic phase. If a patient receives exogenous magnesium during the oliguric phase, severe hypermagnesemia can result, especially if the patient is acidotic. OTHER CAUSES Section 4 of 8
Author Information Introduction Renal Failure Other Causes Effects Of Hypermagnesemia Treatment Of Hypermagnesemia Acknowledgments Bibliography

People often take magnesium-containing medications (eg, antacids, laxatives, rectal enemas). Hypermagnesemia can develop after treatment of drug overdoses with magnesium-containing cathartics, and it also occurs in patients taking magnesium-containing medications for therapeutic purposes; however, most of these patients have normal renal function. If the patient does not ingest a large amount of magnesium but has a gastrointestinal disorder (eg, gastritis, colitis, gastric dilation), absorption may increase. In any case, monitoring serum magnesium levels in patients taking magnesium-containing medications is prudent.

In the treatment of eclampsia, hypermagnesemia is induced deliberately and sometimes can be symptomatic. Occasionally, hypermagnesemia also can occur in the unborn infant. Maternal magnesium therapy can cause neurobehavioral disorders in the unborn child.

Severe hypermagnesemia was described in patients who nearly drowned in the Dead Sea in Jordan, where magnesium levels average 400 mg/dL.

Lithium therapy causes hypermagnesemia by supposedly decreasing urinary excretion, although the mechanism for this is not completely clear.

Familial hypocalciuric hypercalcemia may cause modest elevations in serum magnesium. This autosomal dominant disorder is characterized by very low excretion of calcium and magnesium, and the increase in magnesium reabsorption appears to occur from an abnormal sensitivity of the loop of Henle to magnesium ions.

Hypothyroidism, adrenal insufficiency, and milk alkali syndrome occasionally produce mild elevations of serum magnesium.
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Author Information
Introduction
Renal Failure
Other Causes
Effects Of Hypermagnesemia
Treatment Of Hypermagnesemia
Acknowledgments
Bibliography

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EFFECTS OF HYPERMAGNESEMIA Section 5 of 8
Author Information Introduction Renal Failure Other Causes Effects Of Hypermagnesemia Treatment Of Hypermagnesemia Acknowledgments Bibliography

Symptoms of hypermagnesemia usually are not apparent unless the serum magnesium level is greater than 2 mmol/L. Concomitant hypocalcemia, hyperkalemia, or uremia exaggerate the symptoms of hypermagnesemia at any given level.

Neuromuscular symptoms

These are the most common presenting problems. Hypermagnesemia causes blockage of neuromuscular transmission by preventing presynaptic acetylcholine release and by competitively inhibiting calcium influx into the presynaptic nerve channels via the voltage-dependent calcium channel.

One of the earliest symptoms of hypermagnesemia is deep-tendon reflex reduction. Facial paresthesias also may occur at moderate serum levels.

Muscle weakness is a more severe manifestation, occurring at levels greater than 5 mmol/L. This manifestation can proceed to flaccid paralysis, then to depressed respiration, and, eventually, to apnea.

Conduction system symptoms

Hypermagnesemia depresses the conduction system of the heart and sympathetic ganglia. A moderate increase in serum magnesium can lead to a mild decrease in blood pressure, and a greater concentration may cause severe symptomatic hypotension. Magnesium also is cardiotoxic and, in high concentrations, can cause bradycardia. Occasionally, complete heart block and cardiac arrest may occur at levels greater than 7 mmol/L.

Hypocalcemia

Apparently, this occurs because the secretion of parathyroid hormone (PTH) decreases or because end-organ resistance to PTH occurs. Paralytic ileus develops from smooth-muscle paralysis, and mothers being treated with magnesium for preterm labor suppression are at risk.

Hypermagnesemia may interfere with blood clotting through interference with platelet adhesiveness, thrombin generation time, and clotting time.

Nonspecific symptoms

These symptoms include nausea, vomiting, and cutaneous flushing.

TREATMENT OF HYPERMAGNESEMIA Section 6 of 8
Author Information Introduction Renal Failure Other Causes Effects Of Hypermagnesemia Treatment Of Hypermagnesemia Acknowledgments Bibliography

Prevention of hypermagnesemia is usually possible. Anticipate hypermagnesemia in patients who are receiving magnesium treatment, especially in those with reduced renal function. Initially, withdraw magnesium therapy, which often is enough in patients with mild-to-moderate hypermagnesemia.

In patients with symptomatic hypermagnesemia that is causing cardiac effects or respiratory distress, antagonize the effects by infusing calcium gluconate. Calcium antagonizes the toxic effect of magnesium, and these ions electrically oppose each other at their sites of action. This treatment usually leads to prompt symptomatic improvement.

Drug Name Calcium gluconate (Kalcinate) - Calcium directly antagonizes neuromuscular and cardiovascular effects of magnesium. Use for patients with symptomatic hypermagnesemia that is causing cardiac effects or respiratory distress.
Adult Dose Suggested dosing: 100-300 mg elemental calcium IV diluted in 150 mL D5W over 10 min; initial rate of infusion should be 0.3-2 mg of elemental calcium/kg/h
Pediatric Dose Suggested dosing: 2 mg/kg of elemental calcium IV (about 20 mg/kg of calcium gluconate 10%)
Contraindications Renal calculi, hypercalcemia, hypophosphatemia, renal or cardiac disease, digitalis toxicity
Interactions May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; antagonizes effects of verapamil; high intake of dietary fiber may decrease calcium absorption and levels
Pregnancy B- Usually safe but benefits must outweigh the risks
Precautions Caution in digitalized patients, respiratory failure, acidosis, or severe hyperphosphatemia

Drug Name Glucose and insulin - May help promote magnesium entry into cells. Glucose should be administered with insulin to prevent hypoglycemia. Monitor blood sugar levels frequently.
Adult Dose Suggested dosing: 10 U IV and 50 mL D50W bolus or 500 mL D10W over 1 h
Pediatric Dose Suggested dosing: 0.5-1 g/kg IV followed by 1 U of regular insulin per 3 g glucose
Contraindications Documented hypersensitivity, hypoglycemia
Interactions Medications that may decrease hypoglycemic effects of insulin include acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine, phenothiazines,cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin; medications that may increase hypoglycemic effects of insulin include calcium, ACE inhibitors, alcohol, tetracyclines, beta-blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone
Pregnancy B- Usually safe but benefits must outweigh the risks
Precautions Hyperthyroidism may increase renal clearance of insulin, and more insulin may be required to treat hyperkalemia; hypothyroidism may delay insulin turnover, requiring less insulin to treat hyperkalemia; monitor glucose carefully; dose adjustments of insulin may be necessary in patients diagnosed with renal and hepatic dysfunction

Drug Name Furosemide (Lasix) - May promote excretion of magnesium. Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule.
Adult Dose Suggested dosing: 20-80 mg/d PO/IV/IM; titrate up to 600 mg/d for severe edematous states
Pediatric Dose Suggested PO dosing: 1-2 mg/kg/dose; not to exceed 6 mg/kg/dose; do not administer more often than q6h
Suggested IV/IM dosing: 1 mg/kg slowly under close supervision; not to exceed 6 mg/kg
Contraindications Documented hypersensitivity; hepatic coma, anuria, and state of severe electrolyte depletion
Interactions Metformin decreases concentrations; interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently; increased plasma lithium levels and toxicity are possible when taken concurrently
Pregnancy C- Safety for use during pregnancy has not been established
Precautions Perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter

Hyperkalemia

2007-12-14T18:56:00.000-08:00

Background
Potassium homeostasis

Potassium, the most abundant intracellular cation, is essential for the life of the organism. Potassium is obtained through the diet. Common potassium-rich foods include meats, beans, fruits, and potatoes. Gastrointestinal absorption is complete, resulting in daily excess intake of about 1 mEq/kg/d (60-100 mEq). This excess is excreted through the kidneys (90%) and the gut (10%). Potassium homeostasis is maintained predominantly through the regulation of renal excretion. The most important site of regulation is the cortical collecting tubule where aldosterone receptors are present.

Excretion is increased by the following:

Aldosterone
High sodium delivery to the distal tubule (eg, diuretics)
High urine flow (eg, osmotic diuresis)
High serum potassium level
Delivery of negatively charged ions to the distal tubule (eg, bicarbonate)
Excretion is decreased by the following:

Absence of aldosterone
Low sodium delivery to the distal tubule
Low urine flow
Low serum potassium level
Renal failure
Kidneys adapt to acute and chronic alterations in potassium intake. When potassium intake is chronically high, potassium excretion also is increased. In the absence of potassium intake, obligatory renal losses are 10-15 mEq/d. Thus, chronic losses occur in the absence of any ingested potassium. The kidney maintains a central role in the maintenance of potassium homeostasis, even in the setting of chronic renal failure. Renal adaptive mechanisms allow the kidneys to maintain potassium homeostasis until the glomerular filtration rate drops to less than 15-20 mL/min. Additionally, in the presence of renal failure, the proportion of potassium excreted through the gut increases.

The colon is the major site of gut regulation of potassium excretion. Therefore, potassium levels can remain relatively normal under stable conditions, even with advanced renal insufficiency. However, as renal function worsens, the kidneys may not be capable of handling an acute potassium load. An excess of only 100-200 mEq will increase the serum potassium concentration by about 1 mEq/L.1

Serum potassium level

Potassium is predominantly an intracellular cation; thus, serum potassium levels can be a very poor indicator of total body stores. Potassium moves easily across cell membranes; therefore, serum potassium levels reflect the movement of potassium between intracellular and extracellular fluid compartments as well as total-body potassium homeostasis. Several factors regulate the distribution of potassium between the intracellular and extracellular space.

Glucoregulatory hormones
Insulin enhances potassium entry into cells.
Glucagon impairs potassium entry into cells.
Adrenergic stimuli
Beta-adrenergic stimuli enhance potassium entry into cells, whereas beta-blocking drugs inhibit potassium entry into cells.
Alpha-adrenergic stimuli impair potassium entry into cells.
pH
Alkalosis enhances potassium entry into cells.
Acidosis causes shift of potassium from intracellular space into extracellular space. Inorganic or mineral acid acidoses are more likely to cause a shift of potassium out of the cells than organic acidoses.
Shift from intracellular pool
Acute increase in osmolality, such as hyperglycemia, causes potassium to exit from cells.
Acute cell-tissue breakdown releases potassium into extracellular space.
The 2 sets of regulatory factors, those that regulate total-body homeostasis and those that regulate the distribution of potassium between intracellular and extracellular space, meld to create smooth control of potassium levels throughout the day. For example, a high-protein meal, such as a steak, may contain enough potassium to raise the serum potassium acutely to lethal levels if the potassium remained in the extracellular space. Although renal potassium excretion can increase fairly rapidly, this mechanism easily is overwhelmed by such an acute potassium load.

The acute hyperkalemic effect of an extremely potassium-rich meal is blunted substantially by the release of insulin, which causes potassium to be taken up into cells. The excessive potassium then can be excreted by the kidneys, allowing serum potassium levels to return to normal. This integrated regulatory process is manifested in the diurnal rhythm for renal potassium excretion. The highest excretion occurs at midday, approximately 18 hours after peak potassium ingestion at the evening meal.

Pathophysiology
Any of 3 pathogenetic mechanisms can cause hyperkalemia.

Excessive intake: Excessive potassium intake alone is an uncommon cause of hyperkalemia. The mechanisms for shifting potassium intracellularly and for renal excretion allow a person with normal potassium homeostatic mechanisms to ingest virtually unlimited quantities of potassium. Even parenteral administration of as much as 60 mEq/h for several hours creates only a minimal increase in serum potassium concentration in healthy individuals. Most often, hyperkalemia is caused by a relatively high potassium intake in a patient with impaired mechanisms for the intracellular shift of potassium or renal potassium excretion.

Decreased excretion: Decreased excretion of potassium, especially coupled with excessive intake, is the most common cause of hyperkalemia. The most common causes of decreased renal potassium excretion include renal failure, ingestion of drugs that interfere with potassium excretion (eg, potassium-sparing diuretics, angiotensin-convening enzyme inhibitors, nonsteroidal anti-inflammatory drugs), or impaired responsiveness of the distal tubule to aldosterone (eg, type IV renal tubular acidosis observed with diabetes mellitus, sickle cell disease, chronic partial urinary tract obstruction).

Shift from intracellular to extracellular space: This pathogenetic mechanism alone is a relatively uncommon cause of hyperkalemia but can exacerbate hyperkalemia produced by a high intake or impaired renal excretion. Clinical situations in which this mechanism is the major cause of hyperkalemia include hyperosmolality, rhabdomyolysis, tumor lysis, and succinylcholine administration, which depolarizes the cell membrane and, thus, permits potassium to leave the cells.2 However, more often, mild-to-moderate impairment of intracellular shifting of potassium occurs with insulin deficiency or acute acidosis.

Hyperkalemia may also be caused by IV administration of epsilon amino caproic acid (EACA), a synthetic amino acid. EACA has been found to cause hyperkalemia in studies conducted in dogs. The mechanism of action is presumed to be because of a similarity in structure of EACA to arginine and lysine. These latter amino acids enter the muscle cell in exchange for potassium, thereby leading to an increase in extracellular potassium.3, 4

Regardless of the cause, hyperkalemia produces similar signs and symptoms. Because potassium overwhelmingly is an intracellular cation and various factors can regulate the actual serum potassium concentration, an individual can ingest a substantial potassium load without exhibiting frank hyperkalemia. Conversely, hyperkalemia does not always reflect a true increase in total body potassium stores.

Frequency
United States
Hyperkalemia, defined as serum potassium greater than 5.3 mEq/L, is rare in the general population of healthy individuals. However, certain groups definitely exhibit a higher incidence of hyperkalemia. In patients who are hospitalized, the incidence of hyperkalemia has ranged from 1-10%, depending on the definition of hyperkalemia. Patients at the extremes of life, either premature or elderly, are at high risk. The presence of decreased renal function, genitourinary disease, cancer, severe diabetes, and polypharmacy also predisposes patients to hyperkalemia. Generally, with patients who are hospitalized, drugs are implicated in the development of hyperkalemia in as many as 75% of cases.

Military recruits, individuals with sickle cell traits, and people who abuse drugs are at risk for hyperkalemia due to acute rhabdomyolysis. These cases disproportionately occur in males, probably reflecting the higher muscle mass of males, though an underlying hormonal predisposition cannot be excluded absolutely.

Patients with diabetes constitute a unique high-risk group. They develop defects in all aspects of potassium metabolism. The typical healthy diabetic diet often is high in potassium and low in sodium. Diabetic persons frequently have underlying renal disease and often develop hyporeninemic hypoaldosteronism, impairing renal excretion of potassium. They frequently are placed on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for treatment of diabetic nephropathy, exacerbating the defect in potassium excretion. Finally, persons with diabetes have both insulin deficiency and/or resistance to insulin action, limiting their ability to shift potassium intracellularly. All of these factors combine to render people with diabetes particularly prone to hyperkalemia.

One review of the incidence of hyperkalemia in people with diabetes found that, in an unselected group of diabetic persons treated in a clinic, hyperkalemia (defined as a serum potassium level >5 mEq/L) was found in 15% (270 out of 1764 patients).5 However, fewer than 4% had potassium levels more than 5.4 mEq/L. Clinical risk factors significant in predicting the occurrence of hyperkalemia included renal insufficiency, duration of diabetes mellitus, age, glycosylated hemoglobin levels, and retinopathy. Interestingly, neither the serum glucose level nor the agent for diabetes treatment was significantly correlated.

Significant concern also has been raised about the potential for hyperkalemia in patients taking angiotensin-converting enzyme inhibitors, particularly because the indications for their use in high-risk populations, such as diabetic persons, are broadening rapidly. In one series, the incidence of hyperkalemia in an outpatient clinic was 11%.6 Hyperkalemia occurred in less than 6% of patients with normal renal function. Risk factors for hyperkalemia in patients using angiotensin-converting enzyme inhibitors included elevated BUN and serum creatinine, severe diabetes mellitus, congestive heart failure, peripheral vascular disease, and the use of a long-acting drug.

As the therapy of congestive heart failure has evolved, this growing group of patients also constitute a high-risk group. The factors promoting the development of hyperkalemia in heart failure patients include underlying renal insufficiency due to poor cardiac output and reduced renal blood flow, the high prevalence of diabetes mellitus in the population of heart failure patients, and the growing use of angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone inhibitors, such as spironolactone. The initial studies examining the risk of hyperkalemia in heart failure patients treated with aldosterone inhibitors revealed only a minor increase in hyperkalemia, but later studies showed that as the practice became more widespread, the morbidity and mortality from hyperkalemia have increased.7

International
As in the United States, the incidence of hyperkalemia in the general population has been reported in less than 5% of people. Patients who are hospitalized in countries as diverse as England, Australia, and Israel experience hyperkalemia approximately 10% of the time. Similar to what has been reported in the United States, risk factors include advanced age, significant prematurity, and the presence of renal failure, diabetes mellitus, and heart failure. Additionally, one series documented an increased incidence of hyperkalemia with cancer and gastrointestinal disease.8 Polypharmacy, particularly the use of potassium supplements and potassium-sparing diuretics, in patients with underlying renal insufficiency contributed to hyperkalemia in almost one half of the cases.

Mortality/Morbidity
Hyperkalemia in a patient who is hospitalized is an independent risk factor for death. In one series, 1.4% of patients who were hospitalized (406 out of 29,063 patients) developed hyperkalemia.8

The overall mortality rate in patients with hyperkalemia was 14.3% (58 out of 406 patients), with the risk increasing as potassium level increases.
Twenty-eight percent of patients with a serum potassium level greater than 7 mEq/L died, as opposed to 9% of those with a potassium level less than 6.5 mEq/L. In 7 out of 58 deaths, cause of death was directly attributable to hyperkalemia. Most cases resulting in death were complicated by renal failure.
Interestingly, all patients who died of hyperkalemia had normal potassium levels within the 36 hours prior to death.

Race
No racial predisposition to hyperkalemia appears to exist.

Sex
Men are significantly more prone to hyperkalemia than women. This difference has been noted in several series and stands in contrast to the increased incidence of hypokalemia in women. The reasons for this discrepancy are unknown.

Age
Several series document the increasing tendency for hyperkalemia in patients at the extremes of life, either small premature infants or elderly people, with renal insufficiency playing a significant role in both.

Premature infants are a high-risk group. Relative renal immaturity is likely to be a contributory factor; studies comparing small premature infants who developed hyperkalemia to those who did not indicate that incidence is increased in infants with a lower glomerular filtration rate as estimated by endogenous creatinine clearance. In these small infants, hyperkalemia often occurs within the first 48 hours of life.
Elderly patients are another high-risk group. In several series, an age older than 60 years was an independent risk factor for the development of hyperkalemia in the hospital. Several factors contribute to the increased propensity for elderly people to become hyperkalemic. Renal function tends to deteriorate with age, even in relatively healthy individuals. The glomerular filtration rate decreases by 1 mL/min/y in people older than 30 years. Renal blood flow also decreases. Oral intake declines, resulting in decreased urine flow rates. Plasma renin activity and aldosterone levels also tend to decrease with age, decreasing the ability of the distal nephron to secrete potassium.
Elderly patients are more likely to be taking medications that could interfere with potassium secretion, such as nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, and potassium-sparing diuretics. Elderly individuals who are bedridden often are placed on subcutaneous heparin, which can decrease aldosterone production.

CLINICALSection 3 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References

History
Symptoms are nonspecific and predominantly related to muscular or cardiac function. The most common complaints are weakness and fatigue. Occasionally, a patient may complain of frank muscle paralysis or shortness of breath. Patients also may complain of palpitations or chest pain.

When hyperkalemia is discovered, investigate potential pathophysiologic mechanisms.

For excessive potassium intake, query patients about the following:

Eating disorders - Very unusual diets consisting almost exclusively of high-potassium foods, such as fruits, dried fruits, juices, and vegetables with little to no sodium
Heart healthy diets - Very low-sodium and high-potassium diets recommended for patients with cardiac disease, hypertension, and diabetes mellitus
Use of potassium supplements in over-the-counter herbal supplements, salt substitutes, or prescribed pharmacologic agents - Many patients with renal insufficiency and hypertension have heard the advice to eat a banana a day because the potassium reduces blood pressure. They may not realize that in the case of renal insufficiency and hypertension, this is potentially a life-threatening therapy.
For decreased potassium excretion, query patients about the following:

Ingestion of medications that impair renal potassium excretion
Potassium-sparing diuretics, especially popular in the treatment of cirrhosis and congestive heart failure
Nonsteroidal anti-inflammatory drugs
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
Cyclosporine or tacrolimus
Antibiotics, such as pentamidine or trimethoprim/sulfamethoxazole
EACA3
History of renal insufficiency or renal failure
History of diabetes mellitus, sickle cell disease or trait, or symptoms of lower urinary tract obstruction - These diseases predispose people to type IV renal tubular acidosis, also called hyperkalemic renal tubular acidosis. Type IV renal tubular acidosis also may accompany other tubulointerstitial disorders, such as polycystic kidney disease or amyloidosis. Often, patients with type IV renal tubular acidosis have Hyporeninemic Hypoaldosteronism (ie, decreased aldosterone secondary to suppressed renin levels). One example is diabetes mellitus, where the relative volume overload leads to low renin.
For a shift of potassium into the extracellular space, query patients about the following:

Recurrent episodes of flaccid paralysis
Presence of diabetes mellitus
Use of beta-adrenergic antagonist therapy (eg, for hypertension or angina)
Risk factors for rhabdomyolysis, such as heat stroke, chronic alcoholism, seizures, sudden excessive exertion (eg, in military recruits undergoing basic training), or use of medications that interfere with heat dissipation (eg, tricyclic antidepressants or anesthesia)
Risk factors for tumor lysis syndrome, such as ongoing treatment for widespread lymphoma, leukemia, or other large tumors
Risk factors for hemolysis, such as blood transfusion and sickle cell disease
Other mechanisms

Drugs, such as cyclooxygenase-2 (COX-2) inhibitors9
Ingestion of toad venom (Bufo bufo gargarizans) in southeastern Asian countries
In Southeast Asia, toads are a common folk remedy for strengthening the heart. Bufadienolides, a form of cardiac glycoside that is present in toad venom, have a similar structure and biochemical activity to digitalis and cardenolides, the major plant-derived cardiac glycosides. Bufadienolides cause hyperkalemia via its binding to the alpha subunit of Na+–K+–ATPase, thus inhibiting the reuptake of potassium from the extracellular space.10
This compound has also turned up in some aphrodisiacs and Chinese medications (eg, chan su).
With regard to Western countries, at least 2 cases of poisoning by toad and eggs have been reported in the United States.11

Physical

Vital signs generally are normal, except occasionally in bradycardia due to heart block or tachypnea due to respiratory muscle weakness.
Muscle weakness and flaccid paralysis
Depressed or absent deep tendon reflexes
In general, the results of the physical examination alone do not alert the physician to the diagnosis, except when severe bradycardia is present or muscle tenderness accompanies muscle weakness, suggesting rhabdomyolysis.

Causes
Listed by pathophysiologic mechanisms, causes include increased potassium intake, decreased potassium excretion, or a shift of potassium from the intracellular to the extracellular space. The most common causes are due to decreased excretion. Alone, excessive intake or an extracellular shift is distinctly uncommon. Often, several disorders are present simultaneously.

Increased intake: Alone, this is a rare cause of hyperkalemia because the mechanisms for renal excretion and intracellular disposition are very efficient. In general, a relatively high potassium intake contributes to hyperkalemia in individuals who have impaired renal excretion, impaired intracellular shift, or both.

High-potassium, low-sodium diets
Ingestion of potassium supplements: Ingested amounts would have to be massive as the sole cause of hyperkalemia, but even relatively small amounts can produce hyperkalemia in a patient with impaired renal excretion.
High concentrations of potassium in intravenous fluid preparations, such as total parenteral nutrition
Dietary salt substitutes, penicillin potassium therapy
Decreased excretion: Impaired renal excretion almost always is present when a patient presents with persistent hyperkalemia. Mild degrees of renal failure generally do not result in resting hyperkalemia due to adaptive mechanisms in the kidneys and gastrointestinal tract. However, once the glomerular filtration rate falls below 15-20 mL/min, significant hyperkalemia can occur, even in the absence of an abnormally large potassium load. The simple lack of nephron mass prevents normal potassium homeostasis. Hyperkalemia due to decreased renal excretion can occur when a patient has normal or only mildly decreased renal function as a result of other mechanisms, such as drugs or renal tubular acidosis. Two other causes of decreased excretion of potassium include reduced distal sodium delivery and reduced tubular fluid flow rate.

Drugs

Potassium-sparing diuretics, spironolactone, triamterene, amiloride
Nonsteroidal anti-inflammatory drugs
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
Cyclosporine or tacrolimus
Pentamidine
Trimethoprim/sulfamethoxazole
Heparin
Ketoconazole
Metyrapone
Herbs
Type IV renal tubular acidosis

Diabetes mellitus
Sickle cell disease or trait
Lower urinary tract obstruction
Adrenal insufficiency
Primary Addison syndrome due to autoimmune disease, tuberculosis, or infarct
Enzyme deficiencies
Disorders of steroid metabolism and mineralocorticoid receptors12, 13

21-hydroxylase deficiency in classical form and aldosterone synthase deficiency result in hyperkalemia due to low aldosterone levels.
11-beta hydroxylase deficiency, 3-beta hydroxysteroid dehydrogenase deficiency, and 17 alpha-hydroxylase/17,20-lyase deficiency are generally not characterized by the development of hyperkalemia.
Type 1 pseudohypoaldosteronism is caused by an inactivating mutation of the mineralocorticoid receptor, resulting in impaired potassium secretion due to impaired sodium reabsorption in the distal tubule.14
Gordon syndrome or pseudohypoaldosteronism Type II, characterized by hyperkalemia and hypertension, is caused by mutations in either WNK1 (with no lysine [K]) or WNK4, protein kinases that are localized to the distal tubule and that regulate ion transport in this nephron segment. WNK4 appears to have several roles in regulating sodium, potassium, and chloride transport through transcellular and paracellular pathways.15
Shift of potassium into the extracellular space: Like increased intake, this rarely is the sole cause of hyperkalemia because the mechanisms for renal excretion are very efficient. However, the inability to transport potassium intracellularly exacerbates hyperkalemia in individuals who have impaired renal excretion.

Hyperkalemic periodic paralysis
Insulin deficiency or insulin resistance (ie, type I or type II diabetes mellitus)
Use of beta-adrenergic antagonist therapy (eg, for hypertension or angina)
Tissue breakdown

Rhabdomyolysis
Tumor lysis syndrome
Massive hemolysis
Drugs

Nonselective beta-blockers (inhibits Na-K-ATPase pump)
Digitalis toxicity (inhibits Na-K-ATPase pump)
Succinylcholine (membrane leak)
Inhibition of the sodium pump will impair K entry into the cells and facilitate K exit from the cells.
Hypertonicity may lead to hyperkalemia by 2 mechanisms: loss of intracellular water, resulting in an increased intracellular potassium concentration, favoring a gradient for potassium to move out of the cells; and, as water exits the cells, potassium is swept along with ‘‘solvent drag.' The most common cause of hyperosmolality is hyperglycemia in uncontrolled diabetes mellitus. Other conditions with hypertonicity are hypernatremia and hypertonic mannitol.
Aldosterone deficiency: This is somewhat controversial. Some evidence that long-term aldosterone deficiency impairs cell potassium uptake exists.

DIFFERENTIALSSection 4 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References

Other Problems to be Considered

Pseudohyperkalemia is the term applied to the clinical situation in which in vitro lysis of cellular contents leads to the measurement of a high serum potassium level not reflective of the true in vivo level. This condition occurs most commonly with red cell hemolysis during the blood draw (tourniquet too tight or the blood left sitting too long), severe thrombocytosis (platelet count >1,000,000/mL), or severe leukocytosis (WBC >70,000/mL). Recognizing that when true intravascular hemolysis has occurred, for example, with a transfusion reaction or a hemolytic sickle crisis or drug-induced hemolytic reaction, the measured potassium reflects the true potassium is important.

WORKUPSection 5 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References

Lab Studies

Assess renal function.

Check serum BUN and creatinine levels to determine whether renal insufficiency is present.
Check 24-hour urine for creatinine clearance or estimate the creatinine clearance using the Cockroft-Gault equation to assess whether the degree of renal insufficiency alone explains the hyperkalemia.
The Cockroft-Gault equation is (140 – age)(weight in kg)/(72)(serum creatinine). For women, the answer is multiplied by 0.8.
Estimate the glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) formula, as follows: (GFR (mL/min/1.73 m2) = 186 X (serum creatinine) - 1.154 X (age) - 0.203 X (0.742 if female) X (1.210 if African American) (conventional units).16
Measure urine potassium and sodium concentrations and urine osmolality.

These tests are essential to determine whether impairment of renal excretion is contributing to the hyperkalemia. A urine potassium level less than 20 mEq/L suggests impaired renal excretion. A urine potassium level greater than 40 mEq/L suggests intact renal excretory mechanisms, implying that high intake or failure of cell uptake is the major mechanism for hyperkalemia. However, an isolated urine potassium level often is misleading because the concentration of potassium in the urine is influenced not only by secretion by the cortical collecting tubule but also by the degree of urinary concentration. If the urine osmolality is high (>700 mOsm/kg), then the absolute value of urine potassium concentration can be misleading and suggest that the kidneys are disposing of potassium appropriately.

For example, suppose serum potassium is 6 mEq/L and urine potassium 60 mEq/L. The high urine potassium level suggests appropriate renal potassium excretion. However, the final concentration of potassium in the urine not only is dependent on how much potassium is secreted in response to sodium reabsorption, but it also is dependent on how concentrated the urine is. In the above example, if urine osmolality is 300 mOsm/kg, that is, not concentrated relative to serum, then a measured urine potassium level of 60 mEq/L indeed suggests renal potassium loss. However, if the urine osmolality is 1200 mOsm/kg, that is, concentrated 4-fold relative to the serum, then the potassium concentration in the urine, in the absence of urinary concentration due to water reabsorption, is 15 mEq/L, which is very low.
The conclusion would then be that the kidneys are not appropriately excreting potassium. This adjustment in the evaluation of urinary potassium concentration for the degree of urinary concentration is called calculation of the transtubular potassium gradient (TTKG).
TTKG = (urine K x serum osmolarity)/(serum K x urine osmolarity)

A TTKG less than 3 suggests a lack of aldosterone effect on collecting tubules, that is, kidneys are not excreting potassium appropriately. A TTKG greater than 7 suggests an aldosterone effect, which would be appropriate in the setting of hyperkalemia.
These examples demonstrate that calculation of the TTKG is superior to using the urine potassium alone to assess contribution of decreased renal excretion to hyperkalemia. As useful as this test is, recognizing that it is valid only if 1) the urine osmolality is greater than the serum osmolality, that is, the urine is concentrated relative to the serum, and 2) the urine sodium is greater than 20 mEq/L, that is, distal delivery of sodium is adequate for potassium excretion, is important.
A 24-hour urine potassium measurement rarely is needed to assess renal potassium excretory ability.
Measure complete blood count.

A low hemoglobin and hematocrit (H/H) or abnormal red cell morphology may suggest hemolysis.
Severe leukocytosis or thrombocytosis raises the possibility of pseudohyperkalemia. When in doubt, measure the plasma potassium concentration. Plasma potassium is about the same as serum potassium.
Measure complete metabolic profile.

Low bicarbonate may suggest hyperkalemia due to metabolic acidosis.
Hyperglycemia suggests diabetes mellitus.
Elevated lactic dehydrogenase (LDH), uric acid, phosphate, and alanine aminotransferase (ALT) may suggest tissue breakdown such as in hemolysis, rhabdomyolysis, or tumor lysis.
A creatine kinase (CK) elevation suggests rhabdomyolysis.
Depending on the results of the above laboratory work, the following may be indicated:

Serum cortisol (reference range 8 am 5-25 µg/mL, 4 pm 3-12 µg/mL): Decrease may suggest adrenal insufficiency.
Serum renin and aldosterone (normal supine renin activity 3.2 ± 1 ng/mL/h; normal suppressed aldosterone 5-20 ng/mL): Decrease may suggest adrenal insufficiency.
Fasting blood sugar (reference range 75-115 mg/dL), glycosylated hemoglobin (normal 6.5%), or glucose tolerance test (normal 2 h postprandial value <140 mg/dL): Increase suggests underlying diabetes mellitus.
Assays of 11-beta hydroxylase or 21-hydroxylase: Deficiencies of these enzymes produce syndromes of virilization and generally are recognized in the neonatal period. 11-Beta hydroxylase deficiency is diagnosed by measurement of elevated plasma 11 deoxycortisol levels or increased urinary tetrahydro-ll-deoxycortisol levels. To detect mild cases, adrenocorticotropic hormone (ACTH) stimulation also may be performed to enhance synthesis of these products. 21-Hydroxylase deficiency is detected by the measurement of elevated 17-hydroxyprogesterone levels in blood, generally 90-1200 nmol/L.

Other Tests

Electrocardiogram: This test is vital to assess the physiologic significance of the hyperkalemia. However, ECG changes often do not correlate with the degree of hyperkalemia. ECG changes suggestive of an effect of hyperkalemia on cardiac conduction include (in order of appearance) the following17:

Peaked T waves
Prolongation of the PR interval
Widening of the QRS
Loss of the P wave
Sine wave pattern
Sinus arrest
In patients with organic heart disease and abnormal baseline ECG, bradycardia may be the only new ECG abnormality.18

TREATMENTSection 6 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References

Medical Care
Orient the medical care of patients with hyperkalemia toward 5 different aims.

Evaluation for potential toxicities
Decreasing potassium intake
Increasing potassium uptake into cells
Increasing potassium excretion
Determining the cause to prevent future episodes

Although explicated below in a step-by-step format, these different aspects of hyperkalemia treatment generally are addressed simultaneously. The aggressiveness of therapy is directly related to the rapidity with which hyperkalemia has developed, the absolute level of hyperkalemia, and the evidence of toxicity. The faster the rise of potassium, the higher the level, and the greater the evidence of cardiotoxicity, the more aggressive therapy should be.

The first step is to determine whether the hyperkalemia is producing life-threatening toxicity.
Perform an ECG to look for cardiotoxicity.
Administer intravenous calcium to ameliorate cardiac toxicity, if present.
The second step is to identify and remove sources of potassium intake.
Discontinue oral and parenteral potassium supplements.
Remove potassium-containing salt substitutes.
Examine the patient's diet. Change the diet to a low-potassium tube feed or a 2-g potassium ad-lib diet.
The third step is to enhance potassium uptake by cells to decrease the serum concentration.
Parenteral glucose and insulin infusions are very effective in enhancing potassium uptake. Although glucose stimulates insulin secretion, administration of glucose alone often is not as effective in this clinical situation. The onset of action is within 20-30 minutes, and the duration is variable, from 2-6 hours. Continuous infusions of insulin and glucose-containing intravenous fluids can be used for prolonged effect. Measure glucose and potassium every 2 hours.
Correct metabolic acidosis with sodium bicarbonate. This therapeutic modality is both less effective and less predictable in producing a hypokalemic response due to the variable effect of different forms of metabolic acidosis on the serum potassium level. This particularly is true in patients with chronic renal failure. Nonetheless, if the acidosis is severe, then a trial of parenteral sodium bicarbonate therapy is warranted.
Beta-adrenergic agonists also are quite effective but, perhaps, somewhat more controversial and more likely to produce side effects. In the United States, the most commonly used preparation is nebulized albuterol. The dose for treating hyperkalemia, 10 mg, is substantially higher than the usual dose for the treatment of bronchospasm and requires the assistance of a respiratory therapist. This therapy is highly effective and preferred over alkali therapy in patients with renal failure. Parenteral isoproterenol or albuterol also decrease potassium. However, isoproterenol is not used commonly, and parenteral albuterol is not available in this country. Some investigators have reported tachycardia and chest discomfort using beta-agonist therapy for hyperkalemia. Discontinue beta-adrenergic antagonists.
The fourth step is to increase potassium excretion from the body.
Renal excretion is enhanced easily in the individual with normal kidney function by the administration of parenteral saline accompanied by a loop diuretic such as furosemide.
Discontinue potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and other drugs that inhibit renal potassium excretion.
Monitor volume status and aim to maintain euvolemia.
Renal excretion can be enhanced by administration of aldosterone analogue such as 9-alpha fluorohydrocortisone acetate (Florinef). Florinef especially is helpful in those with hyporeninemia or hypoaldosteronism.
Gastrointestinal excretion can be increased by the use of cation exchange resins such as Kayexalate. Kayexalate can be administered orally or rectally as a retention enema. Because the major site of action for this drug is the colon, rectal administration is preferred for hyperkalemic emergencies.
The effectiveness of this drug is enhanced if the enema can be retained for an hour.
Repeated enemas can be used but, occasionally, cause colon perforation.
The onset of action occurs within 2 hours and is long lasting. The serum potassium level can be decreased by 2 mEq/L with a single enema. Kayexalate administered orally also is quite effective if it is suspended in 70% sorbitol.
Emergency dialysis is a final recourse for patients who are experiencing potentially lethal hyperkalemia that is unresponsive to more conservative measures or for patients who have complete renal failure. Initiation of dialysis often can take several hours; therefore, even if dialysis is contemplated, initiate the other modalities of therapy first.
The final step in the medical management of hyperkalemia is to determine the cause of hyperkalemia in order to prevent future episodes. This should include examination of the following:

Sources of potassium intake
Causes of decreased renal excretion
Causes for impaired cellular uptake

Surgical Care
Surgery generally is not needed for the care of a patient with hyperkalemia.

Patients with metabolic acidosis and consequent hyperkalemia due to ischemic gut obviously require exploration.
Patients with hyperkalemia due to rhabdomyolysis may need surgical decompression of swollen ischemic muscle compartments.
Patients without end-stage renal disease who require hemodialysis for control of hyperkalemia need placement of a hemodialysis catheter for emergent dialysis.

Consultations

For severe hyperkalemia, early consultation with a nephrologist for aid in efficient therapy and plans for dialysis is highly recommended.
For emergency pacemaker placement, the aid of a cardiologist may be required for patients with refractory heart block.

Diet
A low-potassium diet with 2 g of potassium is recommended to minimize potassium intake.

Activity
No restrictions on activity are required unless continuous monitoring for cardiotoxicity is required.

MEDICATIONSection 7 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References

The goals of pharmacotherapy are to reduce potassium levels and morbidity and to prevent complications.

Drug Category: Beta-adrenergic agonists

Through an activation of cyclic adenosine monophosphate (AMP), these agonists stimulate the adenosine triphosphatase (ATPase) pump, thereby shifting potassium into the intracellular compartment.

Drug Name Isoproterenol (Dey-Dose, Isuprel, Arm-a-Med)
Description Has beta1-adrenergic and beta2-adrenergic receptor activity.
Adult Dose 5 mcg/min IV initial, titrate to response; not to exceed 20 mcg/min
Pediatric Dose 0.1 mcg/kg/min IV, titrate to response; not to exceed 2 mcg/min
Contraindications Documented hypersensitivity; tachyarrhythmias, tachycardia, or heart block caused by digitalis intoxication; ventricular arrhythmias that require inotropic therapy; angina pectoris
Interactions Bretylium increases action of vasopressors on adrenergic receptors, which may, in turn, result in arrhythmias; guanethidine may increase effect of direct-acting vasopressors, possibly resulting in severe hypertension; tricyclic antidepressants may potentiate pressor response of direct-acting vasopressors
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions By increasing myocardial oxygen requirements while decreasing effective coronary perfusion, isoproterenol may have a deleterious effect on the injured or failing heart; in some patients presumably with organic disease of the AV node and its branches, isoproterenol paradoxically may worsen heart blocks or precipitate Adams-Stokes attacks; caution in coronary artery disease, coronary insufficiency, diabetes, or hyperthyroidism; if heart rate >110 beats per min, decreasing infusion rate or temporarily discontinuing infusion may be advisable

Drug Name Albuterol (Proventil, Ventolin)
Description Adrenergic agonist that increases plasma insulin concentrations. Increase in insulin may shift potassium into intracellular space.
Adult Dose 10-20 mg nebulized or 0.5 mg IV over 15 min
Pediatric Dose 2.5 mg IV and repeat in 2 h prn
Contraindications Documented hypersensitivity
Interactions Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of
bronchodilatation by albuterol; cardiovascular effects may increase with MAOIs, inhaled
anesthetics, tricyclic antidepressants, and sympathomimetic agents
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders

Drug Category: Calcium salts

Calcium antagonizes cardiotoxicity of hyperkalemia by stabilizing cardiac cell membrane against undesirable depolarization. Has no effect on serum level of potassium. Onset of effect is rapid, within 15 min, but relatively short lived.

Drug Name Calcium gluconate (Kalcinate)
Description Moderates nerve and muscle performance and facilitates normal cardiac function.
Adult Dose 100-300 mg elemental calcium IV diluted in 150 mL D5W over 10 min; initial rate of infusion should be 0.3-2 mg of elemental calcium per kg/h
Pediatric Dose 2 mg/kg of elemental calcium IV (about 20 mg/kg of calcium gluconate 10%)
Contraindications Documented hypersensitivity; renal calculi; hypercalcemia; hypophosphatemia; renal or cardiac disease; digitalis toxicity
Interactions May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; antagonizes effects of verapamil
Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions Caution in patients who are digitalized; respiratory failure; acidosis; severe hyperphosphatemia

Drug Name Calcium chloride
Description Prevents deleterious effects caused by severe hyperkalemia as measured by ECG, pending correction of increased potassium in extracellular fluid. Generally, second choice to calcium gluconate due to irritating effects when administered parenterally.
Adult Dose Known or suspected hyperkalemia (K+ > 6 mEq/L): 2-4 mg/kg IV (10% solution)
Pediatric Dose 0.2 mL (20 mg)/kg of IV (10% solution)
Contraindications Ventricular fibrillation not associated with hyperkalemia; digitalis toxicity; hypercalcemia; renal insufficiency; cardiac disease
Interactions Coadministration with digoxin may cause arrhythmias; may antagonize effects of calcium channel blockers, atenolol, and sodium polystyrene sulfonate
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions Administer slowly (not to exceed 0.5-1 mL/min) to avoid extravasation; hypercalcemia may occur in renal failure

Drug Category: Hormones

Insulin stimulates cellular uptake of potassium, lowering serum potassium level.

Drug Name Insulin (Novolin, Humulin)
Description Stimulates cellular uptake of potassium within 20-30 min. Administer glucose along with insulin to prevent hypoglycemia. Monitor blood sugar levels frequently.
Adult Dose 10 U IV and either 50 mL D50W bolus or 500 mL D10W over 1 h
Pediatric Dose 0.5-1 g/kg IV followed by 1 U of regular insulin per 3 g glucose
Contraindications Documented hypersensitivity; hypoglycemia
Interactions Medications that may decrease hypoglycemic effects of insulin include acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine, phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin; medications that may increase hypoglycemic effects of insulin include calcium, ACE inhibitors, alcohol, tetracyclines, beta-blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone
Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions Hyperthyroidism may increase renal clearance of insulin and may need more insulin to treat hyperkalemia; hypothyroidism may delay insulin turnover, requiring less insulin to treat hyperkalemia; monitor glucose carefully; dose adjustments of insulin may be necessary in patients diagnosed with renal and hepatic dysfunction

Drug Category: Diuretics

Loop diuretics markedly enhance renal potassium excretion, consequently lowering serum levels. Parenterally administered drug has a more rapid onset of action and is preferable in emergent situations. Simultaneous administration of saline can prevent severe volume depletion.

Drug Name Furosemide (Lasix)
Description Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in ascending loop of Henle and distal renal tubule. Individualize dose to patient. Depending on the response, administer at increments of 20-40 mg, no sooner than 6-8 h after the previous dose, until desired diuresis occurs. When treating infants, titrate with increments of 1 mg/kg per dose until a satisfactory effect is achieved. Oral absorption of furosemide is variable from person to person. If rapid and effective therapy is mandated, then IV route is preferred. Occasionally, a continuous infusion of furosemide, as high as 40 mg/h, is used for severe edema but rarely is required for the treatment of hyperkalemia.
Adult Dose 20-80 mg/d PO/IV/IM; titrate as high as 600 mg/d
Pediatric Dose 1-2 mg/kg per dose PO; not to exceed 6 mg/kg per dose; not to administer >q6h
1 mg/kg IV/IM slowly under close supervision; not to exceed 6 mg/kg
Contraindications Documented hypersensitivity; hepatic coma; anuria; state of severe electrolyte depletion
Interactions Metformin decreases furosemide concentrations; furosemide interferes with hypoglycemic effect of
antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides and furosemide; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently with this medication; increased plasma lithium levels and toxicity are possible when taken concurrently
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions Perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter; profound diuresis may occur with fluid and electrolyte loss; caution in hepatic failure

Drug Name Bumetanide (Bumex)
Description Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in ascending loop of Henle and distal renal tubule. Individualize dose to patient. Start at 1-2 mg IV; titrate to as high as 10 mg/d. Rarely, doses as high as 24 mg/d are used for edema but generally are not required for treatment of hyperkalemia.
Adult Dose 0.5-2 mg/dose PO qd/bid; not to exceed 10 mg/d
Alternatively, 0.5-1 mg/dose IV/IM; not to exceed 10 mg/d
Pediatric Dose Not established
Contraindications Documented hypersensitivity; anuria; increasing azotemia
Interactions Decreases effects of indomethacin and probenecid; may increase lithium toxicity
Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions Profound diuresis may occur with fluid and electrolyte loss; caution in hepatic failure; monitor serum sodium, bicarbonate, calcium, magnesium, phosphate, and potassium

Drug Category: Cation exchange resins

Stimulate the exchange of sodium for potassium in the colon, thus increasing intestinal excretion of potassium.

Drug Name Sodium polystyrene sulfonate (Kayexalate)
Description Exchanges sodium for potassium and binds it in the gut, primarily in the large intestine, and decreases total body potassium. Onset of action after oral administration ranges from 2-12 h and is longer when administered rectally.
Adult Dose 25-50 g PO in 25-50 mL sorbitol q6h
25-50 g PR in 25-50 mL sorbitol as retention enema q6h
Pediatric Dose 1 g/kg PO in sorbitol q6h
2 g/kg PR in sorbitol as retention enema q6h
Contraindications Documented hypersensitivity; hypernatremia
Interactions Systemic alkalosis may occur if administered concurrently with magnesium hydroxide, aluminum carbonate or similar antacids, and laxatives
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions Caution when administering to patients who can be affected adversely by a small increase in sodium loads, such as severe hypertension, severe congestive heart failure, and marked edema; constipation, with the possibility of fecal impaction, may occur; treat constipation with 10-20 mL of 70% sorbitol every 2 h or as necessary to produce at least 1-2 watery stools daily

Drug Category: Electrolytes

Used to correct metabolic acidosis if acidosis is severe.

Drug Name Sodium bicarbonate (Neut)
Description Used only when patient is diagnosed with bicarbonate-responsive acidosis, hyperkalemia, tricyclic antidepressant overdose, or phenobarbital overdose. Routine use is not recommended.
To estimate the dose that should be administered may use the following formula: HCO3- (mEq) = 0.5 X weight in kg X (24 - serum HCO3- in mEq/L)
This formula has many limitations; however, the practitioner can determine roughly the amount of bicarbonate required and subsequently titrate against the pH and anion gap.
Adult Dose Generally for parenteral use, 1-2 amps of sodium bicarbonate containing a total of 50-100 mEq is adequate
650-1300 mg PO bid or tid
If the patient has a relatively normal serum bicarbonate level but severe ECG changes of hyperkalemia, then 1 ampule or 50 mEq may be infused q15min, monitoring serum bicarbonate and serum sodium to avoid severe alkalosis and hypernatremia
Alternatively, 2 ampules of sodium bicarbonate (100 mEq) may be added to 1 L 10% dextrose in water and infused at 250-500 mL/h if tolerated
Pediatric Dose Not established
Contraindications Documented hypersensitivity; alkalosis; hypernatremia; hypocalcemia; severe pulmonary edema; unknown abdominal pain
Interactions Urinary alkalinization induced by increased sodium bicarbonate concentrations may cause decreased levels of lithium, tetracyclines, chlorpropamide, methotrexate, and salicylates; increases levels of amphetamines pseudoephedrine, flecainide, anorexiants, mecamylamine, ephedrine, quinidine, and quinine
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions Only use sodium bicarbonate to treat documented metabolic acidosis and hyperkalemia-induced cardiac arrest; can cause alkalosis, decreased plasma potassium, hypocalcemia, and hypernatremia; caution in electrolyte imbalances, such as in patients with CHF, cirrhosis, edema, corticosteroid use, or renal failure; when administering, avoid extravasation because can cause tissue necrosis

FOLLOW-UPSection 8 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References

Further Inpatient Care

Once the potassium level is restored to normal, the potassium-lowering therapies can be discontinued and the serum potassium level can be monitored.
Determine and address the cause for hyperkalemia, including an evaluation of sources of potassium intake, causes for decreased renal excretion, and causes for decreased cell uptake of potassium. Most cases of hyperkalemia are multifactorial, with elements of all 3 causalities contributing to the final picture. In particular, reevaluate the use of potassium supplements (including salt substitutes) in patients with renal insufficiency or in patients taking medications that impair renal excretion of potassium.

Further Outpatient Care

For patients who have a defined and finite reason for hyperkalemia, such as acute exertional rhabdomyolysis or drug-induced hemolysis, serum potassium can be monitored on an infrequent basis. However, for patients who have conditions or medications predisposing them to hyperkalemia and in whom hyperkalemia has developed, monitor serum potassium levels more frequently. Once monthly measurements are indicated for patients at high risk.
For patients who have recurrent or constant hyperkalemia, such as patients with diabetic nephropathy and type IV renal tubular acidosis, chronic therapy with an oral loop diuretic and Kayexalate may be indicated.

In/Out Patient Meds

Loop diuretics often offset mild hyperkalemia without producing significant volume depletion. Once daily furosemide is effective in patients with moderate hyperkalemia and type IV renal tubular acidosis.
Oral Kayexalate is useful in patients with advanced renal failure who are not yet on dialysis or transplant candidates. One or more doses of 15 g/d can control mild-to-moderate hyperkalemia effectively with little inconvenience to patients.
Florinef 0.1 mg PO daily is a useful drug in hyperkalemia associated with mild-to-moderate renal impairment.

Transfer

Transfer patients with severe cardiac toxicity as recorded on ECG to the intensive care unit for continuous monitoring and aggressive therapy.
If a patient requires hemodialysis for hyperkalemia, transfer to a facility with this capability may be required.

Deterrence/Prevention

The most effective prevention of hyperkalemia is through education of patients on the potential causes of hyperkalemia, dietary sources, medical conditions predisposing to hyperkalemia, and contributing medications.
Additionally, repeated review of the patient's medications to identify potential interactions that can cause hyperkalemia is essential.
Some common clinical situations include the following:

Diabetic persons with mild nephropathy who are taking an angiotensin-converting enzyme inhibitor and are on a low-sodium diet
Patients with heart failure who are taking an angiotensin-converting enzyme inhibitor and spironolactone
Patients with chronic renal insufficiency placed on trimethoprim
Recipients of kidney transplants who are taking cyclosporin or tacrolimus and have an abnormal serum creatinine

Complications

Complications of hyperkalemia range from mild ECG changes to cardiac arrest. Weakness is common as well.
Complications of therapy include the following:

Failure to control hyperkalemia
Hypokalemia due to excessively aggressive therapy
Hypercalcemia due to excessive calcium administration
Hypocalcemia from excessive bicarbonate therapy
Chest discomfort or tachycardia due to beta-agonist therapy
Hypoglycemia or hyperglycemia complicating glucose and insulin administration
Metabolic alkalosis and tetany due to excessive sodium bicarbonate administration
Volume depletion, metabolic alkalosis, renal insufficiency, hypocalcemia, hypomagnesemia, and hypophosphatemia due to aggressive loop diuretic use
Colon perforation due to Kayexalate administration

Prognosis

For patients with a defined and transient cause of hyperkalemia, the prognosis is excellent. However, patients who have ongoing risk factors for hyperkalemia are likely to develop recurrent episodes.

Patient Education

Inform patients regarding the following:

Dietary sources of potassium, including salt substitutes
Medications that impair renal excretion, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs, and potassium-sparing diuretics
Clinical situations in which patients might be at risk for the development of hyperkalemia, which include volume depletion and acute renal insufficiency complicating gastrointestinal fluid losses; increasing doses of ACE inhibitors or potassium-sparing diuretics; and addition of a medication that decreases renal excretion or cellular uptake in patients who already are taking such drugs.

hypercalcemia

2007-12-14T18:47:00.000-08:00

Background: Calcium (Ca) plays an important role in intracellular and extracellular metabolism that controls processes, such as nerve conduction, muscle contraction, coagulation, electrolyte and enzyme regulation, and hormone release. Calcium metabolism, in turn, is tightly regulated by a series of hormones that affect not only the entry of calcium into the extracellular space from bone and the GI tract but also control its excretion from the kidneys. Hypercalcemia can be the result of excess entry of calcium into the extracellular fluid (ECF) or of insufficient excretion.

Calcium hemostasis

Ninety-eight percent of body calcium is found in the skeleton; this is closely related to the extracellular concentration of calcium. Intracellular calcium is less than extracellular calcium by a factor of 100,000. Intracellular processes, including the activity of many enzymes, cell division, and exocytosis, are controlled by intracellular calcium. The primary mediator of the intracellular effects of calcium is the calcium-binding regulatory protein, calmodulin.

Plasma calcium is maintained despite its large movements across the gut, bone, kidney, and cells. Changes in calcium ions usually are accompanied by changes in total calcium in the ECF. In plasma, calcium exists in 3 different forms, (1) 50% as ionized or the biologically active form, (2) 45% bound to plasma proteins (mainly albumin), and (3) 5% complexed to phosphate and citrate. Because the proportion of bound calcium varies little within individuals, in the absence of severe acidosis or alkalosis, the amount of albumin is the major factor determining the amount of calcium that is bound.

Very little evidence suggests that intracellular stores of calcium contribute in any way towards plasma calcium homeostasis. An exception is in the parathyroid gland, in which the intracellular concentration increases in response to changes in extracellular concentration, which, in turn, alters the rate of parathyroid hormone (PTH) secretion. Any decrease in extracellular calcium ion concentration leads to an increase in PTH secretion. PTH increases distal renal tubular reabsorption of calcium within minutes and stimulates osteoclast activity, with release of calcium from the skeleton within 1-2 hours. More prolonged PTH elevation stimulates 1alpha-hydroxylase activity in the proximal tubular cells, which leads to 1,25-dihydroxyvitamin D (1,25(OH)2 D3) production. All these mechanisms help to maintain the serum calcium level within normal limits.

A normal serum calcium level is 8-10 mg/dL (2-2.5 mmol/L) with some interlaboratory variation in the reference range, and hypercalcemia is defined as a serum calcium level greater than 10.5 mg/dL (>2.5 mmol/L). Hypercalcemia may be classified based on total serum and ionized calcium levels, as follows:

Mild: Total Ca 10.5-11.9 mg/dL (2.5-3 mmol/L) or Ionized Ca 5.6-8 mg/dL (1.4-2 mmol/L)

Moderate: Total Ca 12-13.9 mg/dL (3-3.5 mmol/L) or Ionized Ca 5.6-8 mg/dL (2-2.5 mmol/L)

Hypercalcemic crisis: Total Ca 14-16 mg/dL (3.5-4 mmol/L) or Ionized Ca 10-12 mg/dL (2.5-3 mmol/L)
Only 1-2% of total body calcium is in the exchangeable form in circulation, and the rest forms part of the skeleton. Only one half of the exchangeable calcium is in the active ionized form with the remainder bound to albumin, globulin, and other inorganic molecules. Protein binding of calcium is influenced by pH with metabolic acidosis leading to increased ionized calcium from reduced protein binding, and alkalosis leading to reduced ionized calcium from increased protein binding. Because calcium binds to albumin and only the unbound (free or ionized) calcium is biologically active, the serum level must be adjusted for abnormal albumin levels.

For every 1-g/dL drop in serum albumin below 4 g/dL, measured serum calcium decreases by 0.8 mg/dL. Therefore, to correct for an albumin level of less than 4 g/dL, one should add 0.8 to the measured value of calcium for each 1-g/dL decrease in albumin. Without this correction, an abnormally high serum calcium level may appear to be normal.

A patient with a serum calcium level of 10.3 mg/dL but an albumin level of 3 g/dL appears to have a normal serum calcium level. However, when corrected for the low albumin, the real serum calcium value is 11.1 mg/dL (10.3 + 0.8), a more obviously abnormal level. Alternatively, serum free (ionized) calcium levels can be directly measured, negating the need for correction for albumin. Corrected calcium can be calculated using the following formula:

Corrected Ca = ([4 - plasma albumin in g/dL] X 0.8 + serum calcium)
Mild cases of hypercalcemia can be asymptomatic and are more often diagnosed incidentally from routine blood tests. Because calcium metabolism normally is tightly controlled by the body, even mild persistent elevations above normal signal disease and should be investigated.

Calcium is controlled by 2 mechanisms. These are (1) controlling or major regulatory hormones and (2) influencing hormones. Controlling or major regulatory hormones include PTH, calcitonin, and vitamin D. Image 1 shows a review of vitamin D metabolism. In the kidney, vitamin D and PTH stimulate the activity of the epithelial calcium channel and the calcium-binding protein (ie, calbindin) to increase active transcellular calcium absorption in the distal convoluted tubule. Influencing hormones include thyroid hormones, growth hormone, and adrenal and gonadal steroids.

Role of the calcium-sensing receptor

The calcium-sensing receptor (CaSR) is a G protein–coupled receptor, which allows the parathyroid chief cells, the thyroidal C cells, and the ascending limb of the loop of Henle (renal tubular epithelial cells) to respond to changes in the extracellular calcium concentration. The ability of the CaSR to sense the serum Ca++ is essential for the appropriate regulation of PTH secretion by the parathyroid glands and for the regulation of passive paracellular calcium absorption in the loop of Henle. Calcitonin secretion and renal tubular calcium reabsorption also are directly regulated by the action of Ca++ on the calcium receptor.

The CaSR gene is located on band 3q13-q21 and encodes a 1078 amino acid protein. CaSR is expressed in many tissues. Three uncommon human disorders are due to abnormalities of the CaSR gene, (1) familial benign hypocalciuric hypercalcemia, (2) neonatal severe hyperparathyroidism, and (3) autosomal dominant hypocalcemia with hypercalciuria.

Pathophysiology: Hypercalcemia affects nearly every organ system in the body, but it particularly affects the CNS and kidneys. Mild hypercalcemia may not produce any symptoms. With modest hypercalcemia, most patients begin to feel fatigued. With higher levels, patients may have anxiety, depression, personality changes, and confusion. With very high levels, somnolence, coma, and death may ensure. The CNS effects are thought to be due to the direct depressant effect of hypercalcemia.

Renal effects include nephrolithiasis from the hypercalciuria. Distal renal tubular acidosis may be observed, and the increase in urine pH and hypocitraturia also may contribute to stone disease. Nephrogenic diabetes insipidus occurs from medullary calcium deposition and inhibition of aquaporin-2, the arginine-vasopressin–regulated water channel. Renal function may decrease due to hypercalcemia-induced renal vasoconstriction or if hypercalcemia is prolonged from calcium deposition (nephrocalcinosis) and interstitial renal disease.

High calcium levels also affect the conducting system of the heart and cause cardiac arrhythmias. Calcium has a positive inotropic effect. Hypercalcemia also causes hypertension, presumably from renal dysfunction and direct vasoconstriction.

The GI manifestations of hypercalcemia include anorexia, nausea, vomiting, and constipation. Prolonged hypercalcemia tends to cause high gastrin levels, which may contribute to peptic ulcer disease and may lead to pancreatitis or the deposition of calcium in any soft tissue. This deposition of calcium is especially prevalent if phosphorous levels also are elevated, as in renal failure.

The severity of symptoms is related not only to the absolute calcium level but also to how fast the rise in serum calcium occurred. Serum calcium levels greater than approximately 15 mg/dL usually are considered to be a medical emergency and must be treated aggressively.

Frequency:

In the US: Hypercalcemia is relatively common and often is mild but of long duration. The incidence of hyperparathyroidism alone is approximately 1-2 cases per 1000 adults. Mild cases are often not diagnosed.
Internationally: Screenings of large groups of patients have found prevalence rates as high as 39 cases per 1000 persons in Scandinavia. Similar screenings in South Africa showed a prevalence of 8 cases per 1000 persons. These higher incidences may reflect underdiagnosis in the United States rather than a true difference in prevalence.
Mortality/Morbidity: Morbidity and mortality from hypercalcemia depend entirely on the cause.

Hypercalcemia from hyperparathyroidism tends to be mild and prolonged. Morbidity is related to the resultant bone disease. Because this condition is underdiagnosed so often, actual morbidity is unknown. Mild hypercalcemia rarely, if ever, leads directly to death.
Hypercalcemia caused by a neoplasm tends to be much more serious. The mechanism of hypercalcemia in malignancy can be from the ectopic production of a PTH-like factor, PTH-related protein (PTHrP), or osteolytic metastases. Often, the hypercalcemia is the immediate cause of death in patients with ectopic PTHrP production. These patients rarely survive more than a few weeks or months. Osteolytic metastases tend to cause morbidity and mortality from nerve compression and other orthopedic complications. These patients may live longer but still have a poor prognosis, especially if their serum calcium levels are very high.
Morbidity and mortality associated with hypercalcemia from other causes are directly related to the underlying cause and tend to be less serious. In these patients, hypercalcemia is a reflection of their disease state and morbidity and mortality depend on control of the underlying disease.
Sex: Some studies show a higher incidence in men compared to women, but this difference tends to diminish with increasing age. One study found the highest incidence to be in women aged 60-63 years.

Age: Hypercalcemia from nearly all causes increases with advancing age, especially the 2 most common causes, malignancy and hyperparathyroidism. However, hypercalcemia may occur in persons of any age.

CLINICAL Section 3 of 11
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History: The mnemonic “stones,” “bones,” “abdominal moans,” and “psychic groans” describes the constellation of symptoms and signs of hypercalcemia. These may be due directly to the hypercalcemia, to increased calcium and phosphate excretion, or to skeleton changes. The history of hypercalcemia is dependent on its cause and the sensitivity of the individual to higher calcium levels. Individuals with mild prolonged hypercalcemia may have mild or no symptoms, or, they may have recurring problems such as kidney stones. Those with more sudden onset and severe hypercalcemia may experience dramatic symptoms, usually including confusion and lethargy, possibly leading quickly to death.

Central nervous system effects include the following:
Lethargy

Weakness
Confusion
Coma
Renal effects include the following:
Polyuria
Nocturia
Dehydration
Renal stones
Renal failure
Gastrointestinal effects include the following:
Constipation
Nausea
Anorexia
Pancreatitis
Gastric ulcer
Cardiac effects include syncope from arrhythmias.
Physical: Most patients with hypercalcemia do not have any specific findings upon physical examination. Those with higher calcium levels may have findings that are more striking. Evidence of the underlying cause may be found, such as a suggestive breast mass in someone with hypercalcemia secondary to malignancy.

Nervous system findings include the following:
Confusion
Hypotonia
Hyporeflexia
Paresis
Coma
Renal findings include the following:
Volume depletion
Signs of renal failure
Gastrointestinal findings include the following:
Fecal impaction (from constipation)
Signs of pancreatitis
Signs of malignancy (eg, enlarged liver or masses)
Cardiac findings include the following:
Arrhythmias
Hypotension
Shortened QT interval
General findings may include band keratopathy, which is calcium precipitation in a horizontal band across the cornea in the palpebral aperture.
Causes: Approximately 90% of cases of hypercalcemia are caused by malignancy or hyperparathyroidism. About 20-30% of patients with cancer have hypercalcemia during the course of the disease, and its detection may signify an unfavorable prognosis. Of the cases due to malignancy, approximately 80% are due to bony metastases, while the other 20% are due to PTHrP effects. Hypercalcemia secondary to malignancy may be classified into 4 types based on the mechanism involved, as follows:

Humoral hypercalcemia of malignancy (HHCM) from an increased secretion of PTHrP. This is the most common form, accounting for up to 80% of cases.

Osteolytic hypercalcemia from osteoclastic activity and bone resorption surrounding the tumor tissue. This is the second most common mechanism, accounting for about 20% of cases.

Secretion of active vitamin D by some lymphomas may be seen.

Ectopic PTH secretion is very rarely seen.
The remaining 10% of cases of hypercalcemia are caused by many different conditions, including vitamin D–related problems, disorders associated with rapid bone turnover, thiazides or renal failure, and, in rare cases, familial causes.

Those related to malignancy (lung, breast, and myeloma are the most common tumors) include the following:
Solid tumor metastases
Solid tumors with humoral effects
Hematologic malignancies
Those related to the parathyroid include the following:
Primary hyperparathyroidism

Solitary adenoma

Generalized hyperplasia

Multiple endocrine neoplasia type 1 or type 2A
Lithium-related release of PTH
Familial cases of high PTH
Those related to vitamin D include the following:
Vitamin D toxicity
Granulomatous disease (especially sarcoidosis)
Those related to high bone turnover include the following:
Hyperthyroidism

Immobilization (especially in Paget disease)

Thiazides

Vitamin A intoxication
Renal failure (milk-alkali syndrome)
Other causes related to particular mechanisms are as follows:
Increased intestinal calcium absorption

Idiopathic infantile hypercalcemia (Williams syndrome)

Vitamin D intoxication

Vitamin A intoxication

Granulomatous disorders, eg, sarcoidosis
Decreased renal calcium excretion

Hyperparathyroidism

Familial hypocalciuric hypercalcemia

Thiazide diuretics
Increased bone resorption

Immobilization

Hyperparathyroidism

Malignancy
Mutations of the calcium-sensing receptor

Familial benign hypocalciuric hypercalcemia

Neonatal severe hyperparathyroidism
Uncertain mechanism

Hypophosphatasia

Subcutaneous fat necrosis

Blue diaper syndrome

Dietary phosphate deficiency
DIFFERENTIALS Section 4 of 11
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Hyperphosphatemia

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WORKUP Section 5 of 11
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Lab Studies:

Malignancy is one of the most common causes and must be excluded. Hyperparathyroidism and other causes of hypercalcemia can coexist with malignancy. If calcium levels have been mildly elevated for months or years, malignancy is an unlikely cause. If calcium levels have been elevated for an unknown duration, the patient should be evaluated for the presence of malignancy. Breast, lung, and kidney cancers should be considered, as should multiple myeloma, lymphoma, and leukemia. Hypercalcemia from malignancy usually is rapidly progressive; thus, rapidly rising calcium levels should increase suspicion of malignancy.
Hyperparathyroidism is the most common cause of hypercalcemia in the population at large and usually is mild, asymptomatic, and sustained for years. Immunoreactive PTH and ionized calcium should be simultaneously measured. PTH levels should be suppressed in hypercalcemia; thus, the presence of normal PTH levels with elevated calcium levels suggests mild hyperparathyroidism. Hyperparathyroidism may be part of multiple endocrine neoplasia type 1, ie, Wermer syndrome.
Other causes of hypercalcemia usually can be distinguished or at least considered on the basis of history and physical examination findings. Measurement of serum phosphate, alkaline phosphatase, serum chloride, serum bicarbonate, and urinary calcium may be useful in some cases. Renal function should be evaluated and thyroid-stimulating hormone should be checked to help rule out hyperthyroidism. In rare cases, measurement of vitamin D and its metabolites and measurement of PTHrP may be necessary.
Imaging Studies:

Chest radiographs always should be performed to help rule out lung cancer or sarcoidosis. Other radiographs should be considered to help evaluate for possible malignancies, metastases, or Paget disease.
Mammograms should be considered to help rule out breast cancer, and CT scan and ultrasound should be considered to help rule out renal cancer.
When a biochemical diagnosis of primary hyperparathyroidism is made, CT scan, ultrasound, MRI, and radionuclide imaging of the parathyroid gland may be helpful to assist with preoperative localization.
Other Tests:

Miscellaneous
Peripheral smear
Serum and urine immunofixation electrophoresis
Procedures:

Tissue histology
Biopsy of solid tumor
Biopsy of bone marrow
TREATMENT Section 6 of 11
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Medical Care: Treatment depends on the severity of symptoms and the underlying cause.

Volume expansion and saline diuresis
Volume depletion results from uncontrolled symptoms leading to decreased intake and enhanced renal sodium loss. This tends to exacerbate or perpetuate the hypercalcemia by increasing Na+ reabsorption in the thick ascending limb of the loop of Henle (TALH). Thus, appropriate volume repletion with isotonic sodium chloride solution is an effective short-term treatment for hypercalcemia.

Once volume is restored, simultaneous administration of loop diuretics blocks Na+ and calcium reabsorption in the TALH.

Replacing ongoing sodium, potassium, chloride, and magnesium losses is important if prolonged sodium chloride and loop diuretic therapy is contemplated.
Mobilization

Immobilization aggravates hypercalcemia.

Whenever possible, weightbearing mobilization should be encouraged.
Reduction of gastrointestinal calcium absorption

Reduction of dietary calcium and vitamin D intake is effective for treating hypercalcemia due to increased intestinal calcium absorption (eg, in idiopathic infantile hypercalcemia, ie, Williams syndrome).

In vitamin D toxicity or extrarenal synthesis of 1,25(OH) D3 (eg, in sarcoidosis), prednisone may help reduce plasma calcium levels by reducing intestinal calcium absorption.

Oral phosphate also can be used to form insoluble calcium phosphate in the gut.
Inhibition of bone resorption

Bisphosphonates inhibit osteoclastic bone resorption and are effective in the treatment of hypercalcemia due to conditions causing increased bone resorption and malignancy-related hypercalcemia.

Pamidronate and etidronate can be given intravenously, while risedronate and alendronate may be effective as oral therapy.

Calcitonin can be given intramuscularly or subcutaneously, but it becomes less effective after several days of use.

Mithramycin blocks osteoclastic function and can be given for severe malignancy-related hypercalcemia. It has significant hepatic, renal, and marrow toxicity.
Dialysis: Peritoneal or hemodialysis against calcium-free or lower calcium concentration dialysate solution is highly effective in lowering plasma calcium levels.
Surgical Care: Surgical care is directed toward reversing the underlying cause of hypercalcemia or repairing the orthopedic damage.

Prolonged hypercalcemia due to hyperparathyroidism may warrant surgical neck exploration and removal of one or more parathyroid glands. This is particularly appropriate if evidence of nephrolithiasis, osteoporosis, reduction of renal function, neuromuscular symptoms, or radiographic bone disease is present.
Hypercalcemia due to malignancy, especially if due to a tumor that is producing PTHrP, may require surgical resection of the tumor.
Orthopedic complications of prolonged hypercalcemia (eg, osteoporosis), complications of Paget disease, or complications of bony metastases may require orthopedic or neurosurgical intervention.
Consultations: Consultation with a surgeon or orthopedist may be required, as indicated.

MEDICATION Section 7 of 11
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The first therapy for symptomatic hypercalcemia is volume repletion. More severe cases require saline infusion with concomitant loop diuretics (eg, furosemide) to increase calcium excretion and lower levels rapidly. Other therapies, outlined below, are for longer-term management. Note, however, that no current therapies generally are effective for long-term outpatient therapy. Definitive treatment often requires surgical management.

Clodronate (not available in the United States) can be given either IV or PO and may represent a better alternative in the future at a dose 1600-2400 mg/d. Ibandronate (not available in the United States) is approximately 50 times more potent than pamidronate and may be given as a single bolus rather than an infusion. Zoledronic acid is 100-850 times more potent than pamidronate and may be given as a bolus rather than an infusion.

Drug Category: Bisphosphonates -- Inhibit bone reabsorption.Drug Name
Pamidronate (Aredia) -- Used after initial hydration to inhibit bone reabsorption and maintain low serum calcium levels, especially in hypercalcemia of malignancy and Paget disease.
Adult Dose Severe hypercalcemia: 90 mg IV over 24 h
Moderate hypercalcemia: 60 mg IV over 4 h or 90 mg IV over 24 h
Pediatric Dose Not established
Contraindications Documented hypersensitivity; hypocalcemia
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Monitor hypercalcemia-related parameters (eg, serum levels of calcium, phosphate, magnesium, and potassium) once treatment begins; adequate intake of calcium and vitamin D are necessary to prevent severe hypocalcemia; caution when administering bisphosphonates in patients with active upper GI problems; do not coadminister with alendronate for osteoporosis in postmenopausal women
Drug Name
Etidronate (Didronel) -- Reduces bone formation and does not alter renal tubular reabsorption of calcium. Does not affect hypercalcemia in patients with hyperparathyroidism.
Adult Dose 7.5 mg/kg/d IV for 3 consecutive d
Pediatric Dose Not established
Contraindications Documented hypersensitivity; hypocalcemia, renal impairment
Interactions Coadministration with calcium-containing products and other multivalent cations decrease absorption
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Monitor hypercalcemia-related parameters (eg, serum levels of calcium, phosphate, magnesium, and potassium); maintain adequate intake of calcium and vitamin D to prevent severe hypocalcemia; caution if active upper GI problems; do not administer with alendronate for osteoporosis in postmenopausal women
Drug Name
Alendronate (Fosamax) -- Available in the United States, but not yet indicated for treatment of hypercalcemia; alendronate probably is useful for long-term prevention of recurrence of hypercalcemia following use of more conventional therapy (ie, hydration and pamidronate). Useful in preventing and treating osteoporosis, which is a complication of prolonged mild hypercalcemia.
Adult Dose Not established; usual starting dose is 40 mg PO qam
Pediatric Dose Not established
Contraindications Documented hypersensitivity; hypocalcemia; abnormalities of the esophagus; inability to stand upright for 30 min
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Must be taken at least 30 min before first food, beverage, or medication of the day and should be taken with large amounts of water; caution in renal impairment
Drug Category: Antineoplastic drugs -- Some agents in this drug class can reduce bone turnover.Drug Name
Gallium nitrate (Ganite) -- Available in the United States. Use should be limited to those with extensive experience in this field (ie, oncologists).
Adult Dose 200 mg/m2 IV infused over 24 h and repeated qd for 5 d
Pediatric Dose Not established
Contraindications Documented hypersensitivity; renal failure
Interactions Nephrotoxic effects increase when administered with amphotericin B or aminoglycosides
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in renal failure
Drug Name
Plicamycin (Mithracin) -- No longer manufactured and distributed in the United States. Inhibits bone resorption. Used only in cases of hypercalcemia due to malignancy; treatment can be repeated if necessary.
Adult Dose 25 mcg/kg IV over 4-6 h
Pediatric Dose Not established
Contraindications Documented hypersensitivity; thrombocytopenia, coagulation disorders, impairment of bone marrow function
Interactions Coadministration with glucagon, calcitonin, and etidronate may increase toxicity
Pregnancy X - Contraindicated in pregnancy
Precautions Monitor platelets, prothrombin, and bleeding times periodically during therapy and for several days after last dose; discontinue therapy if significant prolongation of bleeding times occurs and thrombocytopenia is observed; correct any electrolyte imbalance (especially hypokalemia, hypocalcemia, and hypophosphatemia) prior to treatment
Drug Category: Antidote, hypercalcemia agents -- Inhibit bone resorption and increase renal calcium excretion.Drug Name
Calcitonin (Miacalcin, Osteocalcin) -- Lowers elevated serum calcium in patients with multiple myeloma, carcinoma, or primary hyperparathyroidism. Expect higher response when serum calcium levels are high.
Onset of action is approximately 2 h following injection, and activity lasts for 6-8 h. May lower calcium levels for 5-8 d by approximately 9% if given q12h. IM route is preferred at multiple injection sites with dose >2 mL.
Adult Dose 4-8 IU/kg IM/SC q6-12h
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Hypocalcemia may occur; examine urine sediment during prolonged therapy
Drug Category: Glucocorticoids -- Inhibit cytokine release and have a direct cytolytic effect on some tumor cells.Drug Name
Prednisone (Deltasone, Orasone, Sterapred) -- Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.
Adult Dose 20-50 mg PO bid
Pediatric Dose Not established
Contraindications Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease
Interactions Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use
Drug Category: Minerals -- Phosphate inhibits calcium absorption and promotes calcium deposition. Theorized to help bind dietary calcium, thus rendering it an unabsorbable calcium-phosphorous product, but used rarely.Drug Name
Potassium phosphate (Neutra-Phos-K) -- Increases urinary pyrophosphate and complexes with calcium, thus decreasing urinary calcium level, while pyridoxine results in a reduction of urinary oxalate excretion. All dosage forms must be mixed in 6-8 oz of water. Never give IV. Never give if renal function is abnormal or if serum phosphorous levels are >3 mg/dL.
Adult Dose 250-500 mg phosphorus/8-16 mmol PO tid
Pediatric Dose Not established
Contraindications Abnormal renal function, renal failure, serum phosphorous >4.5 mg/dL; IV administration
Interactions Magnesium-containing and aluminum-containing antacids or sucralfate can act as phosphate binders and decrease serum phosphate levels; potassium-sparing diuretics, ACE inhibitors, and salt substitutes may increase serum phosphate levels
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in patients with renal insufficiency and metabolic alkalosis; admixture of phosphate and calcium in IV fluids can result in calcium phosphate precipitation
Drug Category: Calcimimetic agent -- Binds to and modulates the parathyroid calcium-sensing receptor, increases sensitivity to extracellular calcium, and reduces parathyroid hormone secretion.Drug Name
Cinacalcet (Sensipar) -- Directly lowers parathyroid hormone (PTH) levels by increasing sensitivity of calcium-sensing receptor on chief cell of parathyroid gland to extracellular calcium. Also results in concomitant serum calcium decrease. Indicated for secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and in hypercalcemia with parathyroid carcinoma.
Adult Dose Secondary hyperparathyroidism: 30 mg PO qd initially; titrate upward slowly (no more frequent than q2-4wk intervals) by 30-mg increments to target iPTH of 150-300 pg/mL
Take with meals or immediately following; do not crush, chew, or cut tablets
Hypercalcemia with parathyroid carcinoma: 30 mg PO qd initially; titrate q2-4wk as needed to normalize calcium levels by sequential doses of 30 mg bid, 60 mg bid, 90 mg bid, and 90 mg tid/qid
Take with meals or immediately following; do not crush, chew, or cut tablets
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Interactions Strong CYP450 2D6 inhibitor; may increase serum levels of CYP 2D6 substrates (eg, flecainide, vinblastine, thioridazine, tricyclic antidepressants); coadministration with CYP450 3A4 inhibitors (eg, ketoconazole, erythromycin, itraconazole) may decrease clearance
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Serum calcium reduction may cause lowered seizure threshold, paresthesia, myalgia, cramping, and tetany; monitor calcium and phosphorus levels closely within 1 wk following initial dose or dose changes, and then monthly (secondary hyperparathyroidism) and q2 mo (parathyroid carcinoma); do not initiate treatment if serum calcium level below 8.4 mg/dL; adynamic bone disease may occur if iPTH levels suppressed below 100 pg/mL; caution with hepatic impairment; common adverse effects include nausea and vomiting
FOLLOW-UP Section 8 of 11
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Further Outpatient Care:

In most cases, follow-up care is dictated by the etiology of hypercalcemia.
If the hypercalcemia is related to malignancy, the cause may be obvious in most cases and efforts are directed towards treating the neoplasm.
The role of oral phosphates in the treatment of hypercalcemia is limited and now is increasingly replaced by bisphosphonates. However, when phosphates are used, especially for treating chronic hypercalcemia, attention should be paid to hyperphosphatemia and the calcium and phosphate product because this tends to increase the risk of metastatic calcification.
Dietary restriction of calcium and glucocorticoid administration remains the preferred treatment for hypercalcemia due to sarcoidosis and vitamin D intoxication.

CHOLECYCTITIS

2007-12-08T20:16:00.000-08:00

Background: Cholecystitis is defined as inflammation of the gallbladder that occurs most commonly because of an obstruction of the cystic duct from cholelithiasis. Ninety percent of cases involve stones in the cystic duct (ie, calculous cholecystitis), with the other 10% representing acalculous cholecystitis. Although bile cultures are positive for bacteria in 50-75% of cases, bacterial proliferation may be a result of cholecystitis and not the precipitating factor. Risk factors for cholecystitis mirror those for cholelithiasis and include increasing age, female sex, certain ethnic groups, obesity or rapid weight loss, drugs, and pregnancy.

Acalculous cholecystitis is related to conditions associated with biliary stasis, including debilitation, major surgery, severe trauma, sepsis, long-term total parenteral nutrition (TPN), and prolonged fasting. Other causes of acalculous cholecystitis include cardiac events; sickle cell disease; Salmonella infections; diabetes mellitus; and cytomegalovirus, cryptosporidiosis, or microsporidiosis infections in patients with AIDS.

Pathophysiology: Acute calculous cholecystitis is caused by obstruction of the cystic duct, leading to distention of the gallbladder. As the gallbladder becomes distended, blood flow and lymphatic drainage are compromised, leading to mucosal ischemia and necrosis. A study by Cullen et al (2000) demonstrated the ability of endotoxin to cause necrosis, hemorrhage, areas of fibrin deposition, and extensive mucosal loss, consistent with an acute ischemic insult. Endotoxin also abolished the contractile response to cholecystokinin (CCK), leading to gallbladder stasis.

Although the exact mechanism of acalculous cholecystitis is unclear, a couple of theories exist. Injury may be the result of retained concentrated bile, an extremely noxious substance. In the presence of prolonged fasting, the gallbladder never receives a CCK stimulus to empty; thus, the concentrated bile remains stagnant in the lumen.

Frequency:

In the US: An estimated 10-20% of Americans have gallstones, and as many as one third of these people develop acute cholecystitis. Cholecystectomy for either recurrent biliary colic or acute cholecystitis is the most common major surgical procedure performed by general surgeons, resulting in approximately 500,000 operations annually.
Internationally: Cholelithiasis, the major risk factor for cholecystitis, has an increased prevalence among people of Scandinavian descent, Pima Indians, and Hispanic populations, whereas cholelithiasis is less common among individuals from sub-Saharan Africa and Asia.
Mortality/Morbidity:

Most patients with acute cholecystitis have a complete remission within 1-4 days. However, 25-30% of patients either require surgery or develop some complication.
Patients with acalculous cholecystitis have a mortality rate ranging from 10-50%, which far exceeds the expected 4% mortality rate observed in patients with calculous cholecystitis. Emphysematous cholecystitis has a mortality rate approaching 15%.
Perforation occurs in 10-15% of cases.
Race:

Pima Indian and Scandinavian people have the highest prevalence of cholelithiasis and, consequently, cholecystitis.
Populations at the lowest risk reside in sub-Saharan Africa and Asia.
In the United States, white people have a higher prevalence than black people.
Sex:

Gallstones are 2-3 times more frequent in females than in males, resulting in a higher incidence of calculous cholecystitis in females.
Elevated progesterone levels during pregnancy may cause biliary stasis, resulting in higher rates of gallbladder disease in pregnant females.
Acalculous cholecystitis is observed more often in elderly men.
Age: The incidence of cholecystitis increases with age. The physiologic explanation for the increasing incidence of gallstone disease in the elderly population is unclear. The increased incidence in elderly men has been linked to changing androgen-to-estrogen ratios.

CLINICAL Section 3 of 11
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History:

The most common presenting symptom of acute cholecystitis is upper abdominal pain, often radiating to the tip of the right scapula.
Most patients with acute cholecystitis describe a history of biliary pain. Some patients may have documented gallstones. Acalculous biliary colic also occurs, most commonly in young–to–middle-aged females. The presentation is almost identical to calculous biliary colic with the exception of reference range laboratory values and no findings of cholelithiasis on ultrasound.
Frequently, the pain begins in the epigastric region and then localizes to the right upper quadrant (RUQ). Although the pain may initially be described as colicky, it becomes constant in virtually all cases.
Signs of peritoneal irritation may be present, and, in some patients, the pain may radiate to the right shoulder or scapula.
Nausea and vomiting are generally present, and patients may report fever.
In elderly patients, pain and fever may be absent, and localized tenderness may be the only presenting sign. Patients with acalculous cholecystitis may present similarly to patients with calculous cholecystitis, but acalculous cholecystitis frequently occurs suddenly in severely ill patients without a prior history of biliary colic. Often, patients with acalculous cholecystitis may present with fever and sepsis alone, without history or physical examination findings consistent with acute cholecystitis.
Cholecystitis is differentiated from biliary colic by the persistence of constant severe pain for more than 6 hours.
Physical:

Physical examination may reveal fever, tachycardia, and tenderness in the RUQ or epigastric region, often with guarding or rebound.
A palpable gallbladder or fullness of the RUQ is present in 30-40% of cases.
Jaundice may be noted in approximately 15% of patients.
The absence of physical findings does not rule out the diagnosis of cholecystitis. Many patients present with diffuse epigastric pain without localization to the RUQ. Patients with chronic cholecystitis frequently do not have a palpable RUQ mass secondary to fibrosis involving the gallbladder.
Elderly patients and patients with diabetes frequently have atypical presentations, including absence of fever and localized tenderness with only vague symptoms.
Murphy sign, which is specific but not sensitive for cholecystitis, is described as tenderness and an inspiratory pause elicited during palpation of the RUQ.
Causes:

Risk factors for calculous cholecystitis mirror those for cholelithiasis and include the following:
Female sex
Certain ethnic groups (see Race)
Obesity or rapid weight loss
Drugs (especially hormonal therapy in women)
Pregnancy
Increasing age
Acalculous cholecystitis is related to conditions associated with biliary stasis, to include the following:
Critical illness
Major surgery or severe trauma/burns
Sepsis
Long-term TPN
Prolonged fasting
Other causes of acalculous cholecystitis include the following:
Cardiac events, including myocardial infarction
Sickle cell disease
Salmonella infections
Diabetes mellitus
Patients with AIDS with cytomegalovirus, cryptosporidiosis, or microsporidiosis
Idiopathic cases exist.
DIFFERENTIALS Section 4 of 11
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Abdominal Aortic Aneurysm
Acute Mesenteric Ischemia
Amebic Hepatic Abscesses
Appendicitis
Biliary Colic
Biliary Disease
Cholangiocarcinoma
Cholangitis
Choledocholithiasis
Cholelithiasis
Gallbladder Cancer
Gallbladder Mucocele
Gallbladder Tumors
Gastric Ulcers
Gastritis, Acute
Gastroesophageal Reflux Disease
Hepatitis, Viral
Myocardial Infarction
Nephrolithiasis
Pancreatitis, Acute
Peptic Ulcer Disease
Pneumonia, Bacterial
Pregnancy and Urolithiasis
Pyelonephritis, Acute
Renal Disease and Pregnancy
Renal Vein Thrombosis

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WORKUP Section 5 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Lab Studies:

A retrospective study by Singer (1996) attempted to determine a set of clinical and laboratory parameters that could be used to predict the outcome of hepatobiliary scintigraphy (HBS) in all patients with suspected acute cholecystitis.
The results of the study showed that, in 40 patients with pathologically confirmed acute cholecystitis, fever and leukocytosis were absent at the time of presentation in 36 (90%) and 16 (40%) of the patients, respectively.
The study also found that no combination of laboratory or clinical values was useful in identifying patients at high risk for a positive HBS finding.
Although laboratory criteria are not reliable in identifying all patients with cholecystitis, the following findings may be useful in arriving at the diagnosis:
Leukocytosis with a left shift may be observed in cholecystitis.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are used to evaluate the presence of hepatitis and may be elevated in cholecystitis or with common bile duct obstruction.
Bilirubin and alkaline phosphatase assays are used to evaluate evidence of common duct obstruction.
Amylase/lipase assays are used to evaluate the presence of pancreatitis. Amylase may also be elevated mildly in cholecystitis.
An elevated alkaline phosphatase level is observed in 25% of patients with cholecystitis.
Urinalysis is used to rule out pyelonephritis and renal calculi.
All females of childbearing age should have pregnancy testing.
Imaging Studies:

Radiography (without contrast)
Gallstones may be visualized in 10-15% of cases. This finding only indicates cholelithiasis, with or without active cholecystitis.
Subdiaphragmatic free air cannot originate in the biliary tract, and, if present, it indicates another disease process.
Gas limited to the gallbladder wall or lumen represents emphysematous cholecystitis, usually because of gas-forming bacteria such as Escherichia coli and clostridial and anaerobic streptococci species. Emphysematous cholecystitis is associated with an increased mortality rate and occurs most commonly in males with diabetes and with acalculous cholecystitis.
A diffusely calcified gallbladder (ie, porcelainized) most commonly is associated with carcinoma, although one retrospective study by Towfigh (2001) found no association between partial calcification of the gallbladder and carcinoma.
Other findings may include renal calculi, intestinal obstruction, or pneumonia.
Ultrasonography
Ultrasonography provides greater than 95% sensitivity and specificity for the diagnosis of gallstones more than 2 mm in diameter. Ultrasonography is 90-95% sensitive for cholecystitis and is 78-80% specific. Studies indicate that emergency physicians require minimal training in order to use right upper quadrant ultrasonography in their practice.
Ultrasonographic findings that are suggestive of acute cholecystitis include the following: pericholecystic fluid, gallbladder wall thickening greater than 4 mm, and sonographic Murphy sign. The presence of gallstones also helps to confirm the diagnosis.
Ultrasonography is performed best following a fast of at least 8 hours because gallstones are visualized best in a distended bile-filled gallbladder.
Hepatobiliary scintigraphy (hepatoiminodiacetic acid [HIDA]/diisopropyl iminodiacetic acid [DISIDA])
HBS has been found to be up to 95% accurate in diagnosing acute cholecystitis. The reported sensitivities and specificities of biliary scintigraphy are in the range of 90-100% and 85-95%.
In a typical study, the gallbladder, common bile duct, and small bowel fill within 30-45 minutes.
If the gallbladder is not visualized, intravenous morphine administration can improve the accuracy of HBS by increasing resistance to flow through the sphincter of Oddi, resulting in filling of the gallbladder if the cystic duct is patent. The addition of morphine also reduces the number of false-positive scan results observed in patients who are critically ill and immobilized with viscous bile.
Computed tomography scan and MRI
The sensitivity and specificity of CT/MRI scans for predicting acute cholecystitis have been reported to be greater than 95%. Spiral CT scans and MRI (unlike endoscopic retrograde cholangiopancreatography [ERCP]) have the advantage of being noninvasive, but they have no therapeutic potential and are most appropriate in cases where stones are unlikely.
Findings suggestive of cholecystitis include wall thickening (>4 mm), pericholecystic fluid, subserosal edema (in the absence of ascites), intramural gas, and sloughed mucosa.
A CT/MRI scan is also useful for viewing surrounding structures if the diagnosis is uncertain.
Procedures:

Endoscopic retrograde cholangiopancreatography
ERCP may be useful in patients at high risk for common duct gallstones if signs of common bile duct obstruction are present.
A study performed by Sahai et al (1999) found that ERCP was preferred over endoscopic ultrasound and intraoperative cholangiography for patients at high risk for common duct stones undergoing laparoscopic cholecystectomy.
ERCP allows visualization of the anatomy and may be therapeutic by removing stones from the common bile duct.
Disadvantages include the need for a skilled operator, high cost, and complications such as pancreatitis, which occurs in 3-5% of cases.
Histologic Findings: Edema and venous congestion are early acute changes. Acute cholecystitis is usually superimposed on a histologic picture of chronic cholecystitis. Specific findings include fibrosis, flattening of the mucosa, and chronic inflammatory cells. Mucosal herniations known as Rokitansky-Aschoff sinuses are related to increased hydrostatic pressure and are present in 56% of cases. Focal necrosis and an influx of neutrophils may also be present. Advanced cases may show gangrene or perforation.
TREATMENT Section 6 of 11
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Medical Care: For acute cholecystitis, initial treatment includes bowel rest, intravenous hydration, analgesia, and intravenous antibiotics. For mild cases of acute cholecystitis, antibiotic therapy with a single broad-spectrum antibiotic is adequate. Some options include the following:

Current Sanford guide recommendations include ampicillin (4-6 g/d), ampicillin/sulbactam (Unasyn, 3 g IV/IM q6h), or piperacillin/tazobactam (Zosyn, 3.375 g IV q6h). (In severe life-threatening cases, the Sanford Guide also recommends Primaxin or meropenem.)
For severe cases of acute cholecystitis, gentamicin (3-5 mg/kg/d) with clindamycin (1.8-2.7 g/d) or metronidazole with a third-generation cephalosporin provides adequate coverage.
Bacteria that are commonly associated with cholecystitis include E coli and Bacteroides fragilis and Klebsiella, Enterococcus, and Pseudomonas species.
Emesis can be treated with antiemetics and nasogastric suction.
Because of the rapid progression of acute acalculous cholecystitis to gangrene and perforation, early recognition and intervention are required.
Supportive medical care should include restoration of hemodynamic stability and antibiotic coverage for gram-negative enteric flora and anaerobes if biliary tract infection is suspected.

Daily stimulation of gallbladder contraction with intravenous CCK has been shown by some to effectively prevent the formation of gallbladder sludge in patients receiving TPN.
Surgical Care: Laparoscopic cholecystectomy is the standard of care for the surgical treatment of cholecystitis. Surgery is usually performed after symptoms have subsided but during the hospitalization for acute illness. For elective laparoscopic cholecystectomy, the rate of conversion from a laparoscopic procedure to an open surgical procedure is approximately 5%. The conversion rate for emergency cholecystectomy where perforation or gangrene is present may be as high as 30%.

Immediate cholecystectomy or cholecystotomy is usually reserved for complicated cases in which the patient has gangrene or perforation.
Early operation within 72 hours of admission has both medical and socioeconomic benefits and is the preferred approach for patients treated by surgeons with adequate experience in laparoscopic cholecystectomy.
For patients at high surgical risk, placement of a sonographically guided, percutaneous, transhepatic cholecystostomy drainage tube coupled with the administration of antibiotics may provide definitive therapy.
Results of studies suggest that most patients with acute acalculous cholecystitis can be treated with percutaneous drainage alone.
Contraindications for laparoscopic cholecystectomy include the following:
High risk for general anesthesia
Morbid obesity
Signs of gallbladder perforation such as abscess, peritonitis, or fistula
Giant gallstones or suspected malignancy
End-stage liver disease with portal hypertension and severe coagulopathy
Consultations:

Definitive therapy involves cholecystectomy or placement of a drainage device; therefore, consultation with a surgeon is warranted.
Consultation with a gastroenterologist for consideration of ERCP may also be appropriate if concern exists of choledocholithiasis.
Diet: Patients admitted for cholecystitis should receive nothing by mouth (NPO) because of expectant surgery. However, in uncomplicated cholecystitis, a liquid or low-fat diet may be appropriate until the time of surgery.

MEDICATION Section 7 of 11
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The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Antiemetics -- Patients with cholecystitis frequently experience associated nausea and vomiting. Antiemetics can help to make the patient more comfortable and can prevent fluid and electrolyte abnormalities.Drug Name
Promethazine (Phenergan, Prorex, Anergan) -- For symptomatic treatment of nausea in vestibular dysfunction. Antidopaminergic agent effective in treating emesis. Blocks postsynaptic mesolimbic dopaminergic receptors in brain and reduces stimuli to brainstem reticular system.
Adult Dose 12.5-25 mg PO/IV/IM/PR q4h prn
Pediatric Dose <2 years: Contraindicated
>2 years: 0.25-1 mg/kg PO/IV/IM/PR q4-6h prn
Contraindications Documented hypersensitivity; <2 years (incidences of death due to respiratory depression)
Interactions May have additive effects when used concurrently with other CNS depressants or anticonvulsants; coadministration with epinephrine may cause hypotension
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in patients with cardiovascular disease, impaired liver function, seizures, sleep apnea, and asthma
Drug Name
Prochlorperazine (Compazine) -- May relieve nausea and vomiting by blocking postsynaptic mesolimbic dopamine receptors through anticholinergic effects and depressing reticular activating system. In addition to antiemetic effects, it has the advantage of augmenting hypoxic ventilatory response, acting as a respiratory stimulant at high altitude.
Adult Dose 5-10 mg PO/IM tid/qid; not to exceed 40 mg/d
2.5-10 mg IV q3-4h prn; not to exceed 10 mg/dose or 40 mg/d
25 mg PR bid
Pediatric Dose 2.5 mg PO/PR q8h or 5 mg q12h prn; not to exceed 15 mg/d
IV dosing is not recommended for children
0.1-0.15 mg/kg per dose IM; change to PO as soon as possible
Contraindications Documented hypersensitivity; bone marrow suppression; narrow-angle glaucoma; severe liver or cardiac disease
Interactions Coadministration with other CNS depressants or anticonvulsants may cause additive effects; coadministration with epinephrine may cause hypotension
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Drug-induced Parkinson syndrome or pseudoparkinsonism occurs frequently; akathisia is the most common extrapyramidal reaction in elderly persons; lowers seizure threshold; caution in patients with history of seizures
Drug Category: Antibiotics -- Treatment of cholecystitis with antibiotics should provide coverage against the most common organisms, including E coli, B fragilis, and Klebsiella, Pseudomonas, and Enterococcus species. Current Sanford guide recommendations for the treatment of cholecystitis include Unasyn, Zosyn, and Timentin for non–life-threatening cases of cholecystitis. In life-threatening cases, Sanford recommends Primaxin or meropenem. Alternatives include gentamicin plus clindamycin or metronidazole with a third-generation cephalosporin.Drug Name
Ampicillin and sulbactam (Unasyn) -- Drug combination of beta-lactamase inhibitor with ampicillin. Covers epidermal and enteric flora and anaerobes. Not ideal for nosocomial pathogens.
Adult Dose 1.5 g (1 g ampicillin plus 0.5 g sulbactam) to 3 g (2 g ampicillin plus 1 g sulbactam) IV/IM q6-8h; not to exceed 4 g/d sulbactam or 8 g/d ampicillin
Pediatric Dose 3 months to 12 years: 100-200 mg ampicillin per kg/d (150-300 mg Unasyn) IV divided q6h
>12 years: Administer as in adults
Contraindications Documented hypersensitivity
Interactions Probenecid and disulfiram elevate ampicillin levels; allopurinol decreases ampicillin effects and has additive effects on ampicillin rash; may decrease effects of PO contraceptives
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Adjust dose in renal failure; evaluate rash and differentiate from hypersensitivity reaction
Drug Name
Piperacillin and tazobactam (Zosyn) -- Antipseudomonal penicillin plus beta-lactamase inhibitor. Inhibits biosynthesis of cell wall mucopeptide and is effective during stage of active multiplication.
Adult Dose 3.375 g IV q6h
Pediatric Dose 75 mg/kg IV q6h
Contraindications Documented hypersensitivity; treating severe pneumonia, bacteremia, pericarditis, emphysema, meningitis, and purulent or septic arthritis with a PO penicillin during acute stage
Interactions Tetracyclines may decrease effects of piperacillin; high concentrations of piperacillin may physically inactivate aminoglycosides if administered in same IV line; effects when administered concurrently with aminoglycosides are synergistic; probenecid may increase penicillin levels; high-dose parenteral penicillins may cause increased risk of bleeding
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Perform CBC counts before initiation of therapy and at least weekly during therapy; monitor for liver function abnormalities by measuring AST and ALT levels during therapy; caution in hepatic insufficiencies; perform urinalysis and BUN and creatinine determinations during therapy and adjust dose if values become elevated; monitor blood levels to avoid possible neurotoxic reactions
Drug Name
Gentamicin (Garamycin) -- Aminoglycoside antibiotic for gram-negative coverage. Used in combination with both an agent against gram-positive organisms and one that covers anaerobes.
Not DOC. Consider if penicillins or other less-toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms.
Dosing regimens are numerous; adjust dose based on CrCl and changes in volume of distribution. May be administered IV/IM.
Adult Dose Serious infections and normal renal function: 3 mg/kg/d IV q8h
Loading dose: 1-2.5 mg/kg IV
Maintenance dose: 1-1.5 mg/kg IV q8h
Extended dosing regimen for life-threatening infections: 5 mg/kg/d IV/IM q6-8h
Follow each regimen by at least a trough level drawn on the third or fourth dose (0.5 h before dosing); may draw a peak level 0.5 h after 30-min infusion
Pediatric Dose <5 years: 2.5 mg/kg per dose IV/IM q8h
>5 years: 1.5-2.5 mg/kg per dose IV/IM q8h or 6-7.5 mg/kg/d divided q8h; not to exceed 300 mg/d; monitor as in adults
Contraindications Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Interactions Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; aminoglycosides enhance effects of neuromuscular blocking agents; prolonged respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Narrow therapeutic index (not intended for long-term therapy); caution in renal failure (not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment
Drug Name
Metronidazole (Flagyl) -- Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Used in combination with other antimicrobial agents (except Clostridium difficile enterocolitis).
Adult Dose Loading dose: 15 mg/kg or 1 g for 70-kg adult IV over 1 h
Maintenance dose: 6 h following loading dose, infuse 7.5 mg/kg or 500 mg for 70-kg adult over 1 h q6-8h; not to exceed 4 g/d
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity
Interactions May increase toxicity of anticoagulants, lithium, and phenytoin; cimetidine may increase toxicity of metronidazole; disulfiram reaction may occur with orally ingested ethanol
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Adjust dose in hepatic disease; monitor for seizures and development of peripheral neuropathy
Drug Name
Clindamycin (Cleocin) -- Lincosamide for treatment of serious skin and soft tissue staphylococcal infections. Also effective against aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Adult Dose 150-450 mg/dose PO q6-8h; not to exceed 1.8 g/d
600-1200 mg/d IV/IM divided q6-8h depending on degree of infection
Pediatric Dose 8-20 mg/kg/d PO as hydrochloride or 8-25 mg/kg/d as palmitate divided tid/qid
20-40 mg/kg/d IV/IM divided tid/qid
Contraindications Documented hypersensitivity; regional enteritis; ulcerative colitis; antibiotic-associated colitis; hepatic impairment
Interactions Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects; antidiarrheals may delay absorption
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis by allowing overgrowth of C difficile
Drug Name
Imipenem and cilastatin (Primaxin) -- For treatment of multiple organism infections in which other agents do not have wide spectrum coverage or are contraindicated because of potential for toxicity.
Base initial dose on severity of infection, and administer in equally divided doses.
Adult Dose 250-500 mg q6h IV; not to exceed 3-4 g/d
Alternatively, 500-750 mg q12h IM or intra-abdominally
Pediatric Dose <12 years: Not established; 15-25 mg/kg/dose IV q6h suggested for >3 mo
Fully susceptible organisms: Not to exceed 2 g/d
Moderately susceptible organisms: Not to exceed 4 g/d
Contraindications Documented hypersensitivity
Interactions Coadministration with cyclosporine may increase CNS adverse effects of both agents; coadministration with ganciclovir may result in generalized seizures
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Adjust dose in renal insufficiency
Drug Name
Levofloxacin (Levaquin) -- For pseudomonal infections and infections due to multidrug-resistant gram-negative organisms.
Adult Dose 500 mg PO qd for 7-14 d
Pediatric Dose <18 years: Not recommended
>18 years: Administer as in adults
Contraindications Documented hypersensitivity
Interactions Antacids and iron and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal impairment; superinfections may occur with prolonged or repeated antibiotic therapy
Drug Category: Analgesics -- Pain is a prominent feature of cholecystitis. Classic teaching is that morphine is not the agent of choice because of the possibility of increasing tone at the sphincter of Oddi. Meperidine has been shown to provide adequate analgesia without affecting the sphincter of Oddi and, therefore, is the DOC.Drug Name
Meperidine (Demerol) -- DOC. Analgesic with multiple actions similar to those of morphine. May produce less constipation, smooth muscle spasm, and depression of cough reflex than similar analgesic doses of morphine.
Adult Dose 50-150 mg PO/IV/IM/SC q3-4h prn
Pediatric Dose 1-1.8 mg/kg (0.5-0.8 mg/lb) PO/IV/IM/SC q3-4h prn; not to exceed adult dose
Contraindications Documented hypersensitivity; MAOIs; upper airway obstruction or significant respiratory depression; during labor when delivery of premature infant is anticipated
Interactions Monitor for increased respiratory and CNS depression with coadministration of cimetidine; hydantoins may decrease effects; avoid with protease inhibitors
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Pregnancy category D in prolonged use or high doses at term; caution in patients with head injuries because may increase respiratory depression and CSF pressure (use only if absolutely necessary); use caution postoperatively and in patients with history of pulmonary disease (suppresses cough reflex); increased dosing levels, because of tolerance, may aggravate or cause seizures (even without prior history); adjust dose in patients with renal insufficiency (do not use in patients severe renal dysfunction); normeperidine metabolite accumulation may induce CNS toxicity; monitor closely for morphine-induced seizure activity if prior seizure history
Drug Name
Hydrocodone and acetaminophen (Vicodin, Lortab 5/500, Lorcet-HD) -- Drug combination indicated for moderate to severe pain.
Each tab/cap contains 5 mg hydrocodone and 500 mg acetaminophen.
Adult Dose 1-2 tab/cap PO q4-6h prn
Pediatric Dose <12 years: 10-15 mg/kg/dose acetaminophen PO q4-6h prn; not to exceed 2.6 g/d acetaminophen
>12 years: 750 mg acetaminophen PO q4h; not to exceed 10 mg hydrocodone bitartrate per dose or 5 doses per 24 h
Contraindications Documented hypersensitivity; high-altitude cerebral edema (HACE); elevated intracranial pressure (ICP)
Interactions Coadministration with phenothiazines may decrease analgesic effects; toxicity increases with CNS depressants or tricyclic antidepressants
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Tab contains metabisulfite, which may cause hypersensitivity; caution in patients dependent on opiates because this substitution may result in acute opiate withdrawal symptoms; caution in severe renal or hepatic dysfunction
Drug Name
Oxycodone and acetaminophen (Percocet, Tylox, Roxicet) -- Drug combination indicated for relief of moderate to severe pain.
Each tab/cap contains 5 mg oxycodone and 325 mg acetaminophen.
Adult Dose 1-2 tab/cap PO q4-6h prn
Pediatric Dose 0.05-0.15 mg/kg/dose oxycodone PO; not to exceed 5 mg/dose of oxycodone PO q4-6h prn
Contraindications Documented hypersensitivity
Interactions Phenothiazines may decrease analgesic effects; toxicity increases with coadministration of CNS depressants or tricyclic antidepressants
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Duration of action may increase in elderly persons; be aware of total daily dose of acetaminophen patient is receiving; not to exceed 4000 mg/24h of acetaminophen; higher doses may cause liver toxicity
FOLLOW-UP Section 8 of 11
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Further Inpatient Care:

Objectives during inpatient stay include the following:
Correction of fluid and electrolyte abnormalities
Antibiotics for complicating infections
Performing imaging studies as appropriate (eg, ultrasound, HBS)
Cholecystectomy once the patient is stable or percutaneous transhepatic cholecystostomy drainage in unstable high-risk surgical patients
Further Outpatient Care:

In cases of uncomplicated cholecystitis, outpatient treatment may be appropriate. If a patient can be treated as an outpatient, discharge with antibiotics, appropriate analgesics, and definitive follow-up care. Criteria for outpatient treatment include the following:
Afebrile with stable vital signs
No evidence of obstruction by laboratory values
No evidence of common bile duct obstruction on ultrasound
No underlying medical problems, advanced age, pregnancy, or immunocompromised condition
Adequate analgesia
Reliable patient with transportation and easy access to a medical facility
Prompt follow-up care
In/Out Patient Meds:

For outpatient treatment of uncomplicated cholecystitis, the following medicines may be appropriate:
Prophylactic antibiotic coverage with Levaquin (500 mg PO qd) and Flagyl (500 mg PO bid), which should provide coverage against the most common organisms
Antiemetics such as oral/rectal Phenergan or Compazine to control nausea and prevent fluid and electrolyte disorders
Analgesics such as oral Percocet or Vicodin
Transfer:

Consider patient transfer if the following conditions apply:
Appropriate diagnostic resources are not available.
Higher level of care is required.
Surgeons and/or specialists are unavailable.
Deterrence/Prevention:

Prevention of cholecystitis requires cholecystectomy.
In patients who are unstable, percutaneous transhepatic cholecystostomy drainage may be appropriate.
Some studies have shown that daily CCK administration may help prevent acalculous cholecystitis in patients at risk.
Complications:

Bacterial proliferation within the obstructed gallbladder results in empyema of the organ. Patients with empyema may have a toxic reaction and may have more marked fever and leukocytosis. The presence of empyema frequently requires conversion from laparoscopic to open cholecystectomy.
In rare instances, a large gallstone may erode through the gallbladder wall into an adjacent viscus, usually the duodenum. Subsequently, the stone may become impacted in the terminal ileum or in the duodenal bulb and/or pylorus, causing a gallstone ileus.
Emphysematous cholecystitis occurs in approximately 1% of cases and is noted by the presence of gas in the gallbladder wall from the invasion of gas-producing organisms such as E coli, Clostridia perfringens, and Klebsiella species. This complication is more common in patients with diabetes, has a male predominance, and is acalculous in 28% of cases. Because of a high incidence of gangrene and perforation, emergency cholecystectomy is recommended.
Sepsis
Pancreatitis
Perforation occurs in up to 15% of patients.
Prognosis:

For uncomplicated cholecystitis, the prognosis is excellent, with a very low mortality rate.
In patients who are critically ill with cholecystitis, the mortality rate approaches 50-60%, especially in the setting of gangrene or empyema.
Once complications such as perforation/gangrene develop, the prognosis becomes less favorable. In patients who are critically ill with acalculous cholecystitis and perforation or gangrene, the mortality rate can be as high as 50-60%.
Patient Education:

Patients diagnosed with cholecystitis must be educated regarding causes of their disease, complications if left untreated, and medical/surgical options to treat cholecystitis.
For excellent patient education resources, visit eMedicine's Liver, Gallbladder, and Pancreas Center. Also, see eMedicine's patient education articles Gallstones and Pancreatitis.
MISCELLANEOUS Section 9 of 11
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Medical/Legal Pitfalls:

Delays in making the diagnosis of acute cholecystitis result in a higher incidence of morbidity and mortality. This is especially true for ICU patients who develop acalculous cholecystitis. The diagnosis should be considered and investigated promptly in order to prevent poor outcomes.
Special Concerns:

Pregnancy
RUQ pain in pregnancy can be related to a number of different diagnoses, including preeclampsia, appendicitis, and cholelithiasis.
These patients must have a thorough examination because complications can arise quickly and can be life threatening to both the mother and the unborn child.
Although laparoscopic cholecystectomy is considered safest during the second trimester, it has been performed successfully during all trimesters.
Elderly patients (especially patients with diabetes) may present with vague symptoms and without many key historical and physical findings. Elderly patients may also progress to complicated cholecystitis rapidly and without warning.
The pediatric population may also present without many of the classic findings. Children who are at higher risk for developing cholecystitis include patients with sickle cell disease, seriously ill children, those on prolonged TPN, those with hemolytic conditions, and those with congenital and biliary anomalies.
Patients who are immunocompromised are at increased risk of developing cholecystitis from a number of different infectious sources.

Cirrhosis

2007-12-08T05:50:00.000-08:00

Definition
Cirrhosis represents the final common histologic pathway for a wide variety of chronic liver diseases. The term cirrhosis was first introduced by Laennec in 1826. It is derived from the Greek term scirrhus and is used to describe the orange or tawny surface of the liver seen at autopsy.
Many forms of liver injury are marked by fibrosis. Fibrosis is defined as an excess deposition of the components of extracellular matrix (ie, collagens, glycoproteins, proteoglycans) within the liver. This response to liver injury potentially is reversible. In contrast, in most patients, cirrhosis is not a reversible process.
Cirrhosis is defined histologically as a diffuse hepatic process characterized by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules. The progression of liver injury to cirrhosis may occur over weeks to years. Indeed, patients with hepatitis C may have chronic hepatitis for as long as 40 years before progressing to cirrhosis.
Often a poor correlation exists between histologic findings and the clinical picture. Some patients with cirrhosis are completely asymptomatic and have a reasonably normal life expectancy. Other individuals have a multitude of the most severe symptoms of end-stage liver disease and have a limited chance for survival. Common signs and symptoms may stem from decreased hepatic synthetic function (eg, coagulopathy), decreased detoxification capabilities of the liver (eg, hepatic encephalopathy), or portal hypertension (eg, variceal bleeding).
Epidemiology
Chronic liver disease and cirrhosis result in about 35,000 deaths each year in the United States. Cirrhosis is the ninth leading cause of death in the United States and is responsible for 1.2% of all US deaths. Many patients die from the disease in their fifth or sixth decade of life. Each year, 2000 additional deaths are attributed to fulminant hepatic failure (FHF). FHF may be caused viral hepatitis (eg, hepatitis A and B), drugs (eg, acetaminophen), toxins (eg, Amanita phalloides, the yellow death-cap mushroom), autoimmune hepatitis, Wilson disease, and a variety of less common etiologies. Cryptogenic causes are responsible for one third of fulminant cases. Patients with the syndrome of FHF have a 50-80% mortality rate unless they are salvaged by liver transplantation.
Etiology
Alcoholic liver disease once was considered to be the predominant cause of cirrhosis in the United States. Hepatitis C has emerged as the nation's leading cause of both chronic hepatitis and cirrhosis.
Many cases of cryptogenic cirrhosis appear to have resulted from nonalcoholic fatty liver disease (NAFLD). When cases of cryptogenic cirrhosis are reviewed, many patients have one or more of the classical risk factors for NAFLD: obesity, diabetes, and hypertriglyceridemia. It is postulated that steatosis may regress in some patients as hepatic fibrosis progresses, making the histologic diagnosis of NAFLD difficult.
Up to one third of Americans have NAFLD. About 2-3% of Americans have nonalcoholic steatohepatitis (NASH), where fat deposition in the hepatocyte is complicated by liver inflammation and fibrosis. It is estimated that 10% of patients with NASH will ultimately develop cirrhosis. NAFLD and NASH are anticipated to have a major impact on the United States' public health infrastructure over the next decade.
Most common causes of cirrhosis in the United States
Hepatitis C (26%)
Alcoholic liver disease (21%)
Hepatitis C plus alcoholic liver disease (15%)
Cryptogenic causes (18%)
Hepatitis B, which may be coincident with hepatitis D (15%)
Miscellaneous (5%)
Miscellaneous causes of chronic liver disease and cirrhosis
Autoimmune hepatitis
Primary biliary cirrhosis
Secondary biliary cirrhosis (associated with chronic extrahepatic bile duct obstruction)
Primary sclerosing cholangitis
Hemochromatosis
Wilson disease
Alpha-1 antitrypsin deficiency
Granulomatous disease (eg, sarcoidosis)
Type IV glycogen storage disease
Drug-induced liver disease (eg, methotrexate, alpha methyldopa, amiodarone)
Venous outflow obstruction (eg, Budd-Chiari syndrome, veno-occlusive disease)
Chronic right-sided heart failure
Tricuspid regurgitation
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PATHOPHYSIOLOGY OF HEPATIC FIBROSIS
Section 3 of 10
Author Information Definition, Epidemiology, And Etiology Of Cirrhosis Pathophysiology Of Hepatic Fibrosis Portal Hypertension Ascites Hepatic Encephalopathy Other Manifestations Of Cirrhosis; Assessment Of Severity Of Cirrhosis Treatment Of Cirrhosis Liver Transplantation Bibliography
The development of hepatic fibrosis reflects an alteration in the normally balanced processes of extracellular matrix production and degradation. Extracellular matrix, the normal scaffolding for hepatocytes, is composed of collagens (especially types I, III, and V), glycoproteins, and proteoglycans. Stellate cells, located in the perisinusoidal space, are essential for the production of extracellular matrix. Stellate cells, which were once known as Ito cells, lipocytes, or perisinusoidal cells, may become activated into collagen-forming cells by a variety of paracrine factors. Such factors may be released by hepatocytes, Kupffer cells, and sinusoidal endothelium following liver injury. As an example, increased levels of the cytokine transforming growth factor beta1 (TGF-beta1) are observed in patients with chronic hepatitis C and those with cirrhosis. TGF-beta1, in turn, stimulates activated stellate cells to produce type I collagen.
Increased collagen deposition in the space of Disse (the space between hepatocytes and sinusoids) and the diminution of the size of endothelial fenestrae lead to the capillarization of sinusoids. Activated stellate cells also have contractile properties. Both capillarization and constriction of sinusoids by stellate cells contribute to the development of portal hypertension.
Future drug strategies to prevent fibrosis may focus on reducing hepatic inflammation, inhibiting stellate cell activation, inhibiting the fibrogenic activities of stellate cells, and stimulating matrix degradation.

PORTAL HYPERTENSION
Section 4 of 10
Author Information Definition, Epidemiology, And Etiology Of Cirrhosis Pathophysiology Of Hepatic Fibrosis Portal Hypertension Ascites Hepatic Encephalopathy Other Manifestations Of Cirrhosis; Assessment Of Severity Of Cirrhosis Treatment Of Cirrhosis Liver Transplantation Bibliography
Causes
The normal liver has the ability to accommodate large changes in portal blood flow without appreciable alterations in portal pressure. Portal hypertension results from a combination of increased portal venous inflow and increased resistance to portal blood flow.
Patients with cirrhosis demonstrate increased splanchnic arterial flow and, accordingly, increased splanchnic venous inflow into the liver. Increased splanchnic arterial flow is explained partly by decreased peripheral vascular resistance and increased cardiac output in the patient with cirrhosis. Nitric oxide appears to be the major driving force for this phenomenon. Furthermore, evidence for splanchnic vasodilation exists. Putative splanchnic vasodilators include glucagon, vasoactive intestinal peptide, substance P, prostacyclin, bile acids, tumor necrosis factor-alpha (TNF-alpha), and nitric oxide.
Increased resistance across the sinusoidal vascular bed of the liver is caused by both fixed factors and dynamic factors. Two thirds of intrahepatic vascular resistance is explained by fixed changes in the hepatic architecture. Such changes include the formation of regenerating nodules and the production of collagen by activated stellate cells. Collagen, in turn, is deposited within the space of Disse.
Dynamic factors account for one third of intrahepatic vascular resistance. Stellate cells serve as contractile cells for adjacent hepatic endothelial cells. The nitric oxide produced by the endothelial cells, in turn, controls the relative degree of vasodilation or vasoconstriction produced by the stellate cells. In cirrhosis, decreased local production of nitric oxide by endothelial cells permits stellate cell contraction, with resulting vasoconstriction of the hepatic sinusoid. (This contrasts with the peripheral circulation where there are high circulating levels of nitric oxide in cirrhosis.) Increased local levels of vasoconstricting chemicals, like endothelin, may also contribute to sinusoidal vasoconstriction.
The portal hypertension of cirrhosis is caused by the disruption of hepatic sinusoids. However, portal hypertension may be observed in a variety of noncirrhotic conditions. Prehepatic causes include splenic vein thrombosis and portal vein thrombosis. These conditions commonly are associated with hypercoagulable states and with malignancy (eg, pancreatic cancer).
Intrahepatic causes of portal hypertension are divided into presinusoidal, sinusoidal, and postsinusoidal conditions.
The classic form of presinusoidal disease is caused by the deposition of Schistosoma oocytes in presinusoidal portal venules, with the subsequent development of granulomata and portal fibrosis. Schistosomiasis is the most common noncirrhotic cause of variceal bleeding worldwide. Schistosoma mansoni infection is described in Puerto Rico, Central and South America, the Middle East, and Africa. Schistosoma japonicum is described in the Far East. Schistosoma hematobium, observed in the Middle East and Africa, can produce portal fibrosis but more commonly is associated with urinary tract deposition of eggs.
The classic sinusoidal cause of portal hypertension is cirrhosis.
The classic postsinusoidal condition is an entity known as veno-occlusive disease. Obliteration of the terminal hepatic venules may result from ingestion of pyrrolizidine alkaloids in Comfrey tea or Jamaican bush tea and following the high-dose chemotherapy that precedes bone marrow transplantation.
Posthepatic causes of portal hypertension may include chronic right-sided heart failure and tricuspid regurgitation and obstructing lesions of the hepatic veins and inferior vena cava. These latter conditions, and the symptoms they produce, are termed Budd-Chiari syndrome. Predisposing conditions include hypercoagulable states, tumor invasion into the hepatic vein or inferior vena cava, and membranous obstruction of the inferior vena cava. Inferior vena cava webs are observed most commonly in South and East Asia and are postulated to be due to nutritional factors.
Symptoms of Budd-Chiari syndrome are attributed to decreased outflow of blood from the liver, with resulting hepatic congestion and portal hypertension. These symptoms include hepatomegaly, abdominal pain, and ascites. Cirrhosis only ensues later in the course of disease. Differentiating Budd-Chiari syndrome from cirrhosis by history or physical examination may be difficult. Thus, Budd-Chiari syndrome must be included in the differential diagnosis of conditions that produce ascites and varices. Hepatic vein patency is checked most readily by performing an abdominal ultrasound with Doppler examination of the hepatic vessels. Abdominal CT scan with intravenous contrast, abdominal MRI, and visceral angiography also may provide information regarding the patency of hepatic vessels.
Measurement of portal hypertension
Widespread use of the transjugular intrahepatic portosystemic shunt (TIPS) procedure in the 1990s for the management of variceal bleeding led to a resurgence of clinicians' interest in measuring portal pressure. During angiography, a catheter may be placed selectively via either the transjugular or transfemoral route into the hepatic vein. In the healthy patient, free hepatic vein pressure (FHVP) is equal to inferior vena cava pressure. FHVP is used as an internal zero reference point. Wedged hepatic venous pressure (WHVP) is measured by inflating a balloon at the catheter tip, thus occluding a hepatic vein branch. Measurement of the WHVP provides a close approximation of portal pressure (PP). The WHVP actually is slightly lower than the PP because of some dissipation of pressure in the sinusoidal bed. The WHVP and PP both are elevated in patients with sinusoidal portal hypertension, as is observed in cirrhosis.
Consequences of portal hypertension
Hepatic venous pressure gradient (HVPG) is defined as the difference in pressure between the portal vein and the inferior vena cava. Thus, HVPG is equal to the WHVP value minus the FHVP value (ie, HVPG=WHVP-FHVP). Normal HVPG is defined as 3-6 mm Hg. Portal hypertension is defined as a sustained elevation of portal pressure above normal. An HVPG of 8 mm Hg is believed to be the threshold above which ascites potentially can develop. An HVPG of 12 mm Hg is the threshold for the potential formation of varices. High portal pressures may predispose patients to an increased risk of variceal hemorrhage.
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ASCITES
Section 5 of 10
Author Information Definition, Epidemiology, And Etiology Of Cirrhosis Pathophysiology Of Hepatic Fibrosis Portal Hypertension Ascites Hepatic Encephalopathy Other Manifestations Of Cirrhosis; Assessment Of Severity Of Cirrhosis Treatment Of Cirrhosis Liver Transplantation Bibliography
Ascites is defined as an accumulation of excessive fluid within the peritoneal cavity and may be a complication of both hepatic and nonhepatic diseases. The 4 most common causes of ascites in North America and Europe are cirrhosis, neoplasm, congestive heart failure, and tuberculous peritonitis.
In the past, ascites was classified as being a transudate or an exudate. In transudative ascites, fluid was said to cross the liver capsule because of an imbalance in Starling forces. In general, ascites protein was less than 2.5 g/dL. Classic causes of transudative ascites are portal hypertension secondary to cirrhosis and congestive heart failure.
Table 1. Nonperitoneal Causes of Ascites
Cause of Nonperitoneal Ascites
Examples
Intrahepatic portal hypertension
CirrhosisFulminant hepatic failureVeno-occlusive disease
Extrahepatic portal hypertension
Hepatic vein obstruction (ie, Budd-Chiari syndrome)Congestive heart failure
Hypoalbuminemia
Nephrotic syndromeProtein-losing enteropathy Malnutrition
Miscellaneous disorders
MyxedemaOvarian tumorsPancreatic ascitesBiliary ascites
Chylous
Secondary to malignancySecondary to traumaSecondary to portal hypertension
In exudative ascites, fluid was said to weep from an inflamed or tumor-laden peritoneum. In general, ascites protein was greater than 2.5 g/dL. Examples included peritoneal carcinomatosis and tuberculous peritonitis.
Table 2. Peritoneal Causes of Ascites
Causes of Peritoneal Ascites
Examples
Malignant ascites
Primary peritoneal mesotheliomaSecondary peritoneal carcinomatosis
Granulomatous peritonitis
Tuberculous peritonitisFungal and parasitic infections (eg, Candida,Histoplasma, Cryptococcus, Schistosoma mansoni,Strongyloides, Entamoeba histolytica)SarcoidosisForeign bodies (ie, talc, cotton and wood fibers, starch, barium)
Vasculitis
Systemic lupus erythematosusHenoch-Schönlein purpura
Miscellaneous disorders
Eosinophilic gastroenteritisWhipple diseaseEndometriosis
Attributing ascites to diseases of nonperitoneal or peritoneal origin is more useful. Thanks to the work of Bruce Runyon, the serum-ascites albumin gradient (SAAG) has come into common clinical use for differentiating these conditions. Nonperitoneal diseases produce ascites with a SAAG greater than 1.1 g/dL (see Table 1).
Chylous ascites, caused by obstruction of the thoracic duct or cisterna chyli, most often is due to malignancy (eg, lymphoma) but occasionally is observed postoperatively and following radiation injury. Chylous ascites also may be observed in the setting of cirrhosis. The ascites triglyceride concentration is greater than 110 mg/dL. In addition, ascites triglyceride concentrations are greater than those observed in plasma. Patients should be placed on a low-fat diet, which is supplemented by medium-chain triglycerides. Treatment with diuretics and large-volume paracentesis may be required. Peritoneal diseases produce ascites with a SAAG of less than 1.1 g/dL (see Table 2).
The role of portal hypertension in the pathogenesis of cirrhotic ascites
The formation of ascites in cirrhosis depends on the presence of unfavorable Starling forces within the hepatic sinusoid and on some degree of renal dysfunction. Patients with cirrhosis are observed to have increased hepatic lymphatic flow.
Fluid and plasma proteins diffuse freely across the highly permeable sinusoidal endothelium into the space of Disse. Fluid in the space of Disse, in turn, enters the lymphatic channels that run within the portal and central venous areas of the liver.
Because the transsinusoidal oncotic gradient is approximately zero, the increased sinusoidal pressure that develops in portal hypertension increases the amount of fluid entering the space of Disse. When the increased hepatic lymph production observed in portal hypertension exceeds the ability of the cisterna chyli and thoracic duct to clear the lymph, fluid crosses into the liver interstitium. Fluid may then extravasate across the liver capsule into the peritoneal cavity.
The role of renal dysfunction in the pathogenesis of cirrhotic ascites
Patients with cirrhosis experience sodium retention, impaired free water excretion, and intravascular volume overload. These abnormalities may occur even in the setting of a normal glomerular filtration rate. To some extent, these abnormalities are due to increased levels of renin and aldosterone.
The peripheral arterial vasodilation hypothesis states that splanchnic arterial vasodilation, driven by high nitric oxide levels, leads to intravascular underfilling. This leads to stimulation of the renin-angiotensin system and the sympathetic nervous system and to antidiuretic hormone release. These events are followed by an increase in sodium and water retention, by an increase in plasma volume, and by the overflow of ascites into the peritoneal cavity.
Hepatorenal syndrome
This syndrome represents a continuum of renal dysfunction that may be observed in patients with cirrhosis and is caused by the vasoconstriction of large and small renal arteries and the impaired renal perfusion that results. The syndrome may represent an imbalance between renal vasoconstrictors and vasodilators. Plasma levels of a number of vasoconstricting substances are elevated in patients with cirrhosis and include angiotensin, antidiuretic hormone, and norepinephrine. Renal perfusion appears to be protected by vasodilators, including prostaglandins E2 and I2 and atrial natriuretic factor. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis. They may potentiate renal vasoconstriction, with a resulting drop in glomerular filtration. Thus, the use of NSAIDs is contraindicated in patients with decompensated cirrhosis.
Most patients with hepatorenal syndrome are noted to have minimal histological changes in the kidneys. Kidney function usually recovers when patients with cirrhosis and hepatorenal syndrome undergo liver transplantation. In fact, a kidney donated by a patient dying from hepatorenal syndrome functions normally when transplanted into a renal transplant recipient.
Hepatorenal syndrome progression may be slow (type II) or rapid (type I). Type I disease frequently is accompanied by rapidly progressive liver failure. Hemodialysis offers temporary support for such patients. These individuals are salvaged only by performance of liver transplantation. Exceptions to this rule are the patients with FHF or severe alcoholic hepatitis who spontaneously recover both liver and kidney function. In type II hepatorenal syndrome, patients may have stable or slowly progressive renal insufficiency. Many such patients develop ascites that is resistant to management with diuretics.
Hepatorenal syndrome is diagnosed when a creatinine clearance less than 40 mL/min is present or when a serum creatinine greater than 1.5 mg/dL, urine volume less than 500 mL/d, and urine sodium less than 10 mEq/L are present. Urine osmolality is greater than plasma osmolality. In hepatorenal syndrome, renal dysfunction cannot be explained by preexisting kidney disease, prerenal azotemia, the use of diuretics, or exposure to nephrotoxins. Clinically, the diagnosis may be reached if central venous pressure is determined to be normal or if no improvement of renal function occurs following the infusion of at least 1.5 L of a plasma expander.
Nephrotoxic medications, including aminoglycoside antibiotics, should be avoided in patients with cirrhosis. Patients with early hepatorenal syndrome may be salvaged by aggressive expansion of intravascular volume with albumin and fresh frozen plasma and by avoidance of diuretics. Administration of oral prostaglandins may be beneficial, but this point is controversial. Use of renal-dose dopamine is not effective.
Recently, a number of investigators have employed systemic vasoconstrictors in an attempt to reverse the effects of nitric oxide on peripheral arterial vasodilation. In Europe, administration of intravenous terlipressin (an analog of vasopressin not available in the United States) improved the renal dysfunction of patients with hepatorenal syndrome. A combination of midodrine (an oral alpha agonist), subcutaneous octreotide, and albumin infusion also improved renal function in a small series of patients with hepatorenal syndrome.
Clinical features of ascites
Ascites is suggested by the presence of a number of findings upon physical examination, which are abdominal distention, bulging flanks, shifting dullness, and elicitation of a "puddle sign" in patients in the knee-elbow position. A fluid wave may be elicited in patients with massive tense ascites. However, physical examination findings are much less sensitive than performing abdominal ultrasonography, which can detect as little as 30 mL of fluid. Furthermore, ultrasound with Doppler can help assess the patency of hepatic vessels. Factors associated with worsening of ascites include excess fluid or salt intake, malignancy, venous occlusion (eg, Budd-Chiari syndrome), progressive liver disease, and spontaneous bacterial peritonitis (SBP).
Spontaneous bacterial peritonitis
SBP is observed in 15-26% of patients hospitalized with ascites. The syndrome arises most commonly in patients whose low-protein ascites (<1 g/dL) contains low levels of complement, resulting in decreased opsonic activity. SBP appears to be caused by the translocation of GI tract bacteria across the gut wall and also by the hematogenous spread of bacteria. The most common causative organisms are Escherichia coli, Streptococcus pneumoniae, Klebsiella species, and other gram-negative enteric organisms.
Classic SBP is diagnosed by the presence of neutrocytosis, which is defined as greater than 250 polymorphonuclear (PMN) cells per mm3 of ascites, in the setting of a positive ascites culture. Culture-negative neutrocytic ascites is observed more commonly. Both conditions represent serious infections that carry a 20-30% mortality rate.
The most commonly used regimen in the treatment of SBP is a 5-day course of cefotaxime at 1-2 g intravenously every 8 hours. Alternatives include oral ofloxacin and other intravenous antibiotics with activity against gram-negative enteric organisms. Many authorities advise repeat paracentesis in 48-72 hours to document a decrease in the ascites PMN count to less than 250 cells/mm3 and to ensure the efficacy of therapy.
Once SBP develops, patients have a 70% chance of redeveloping the condition within 1 year. Prophylactic antibiotic therapy can reduce the recurrence rate of SBP to 20%. Some of the regimens used in the prophylaxis of SBP include norfloxacin at 400 mg orally every day and trimethoprim-sulfamethoxazole at 1 double-strength tablet 5 days per week.
Therapy with norfloxacin at 400 mg orally twice per day for 7 days can reduce serious bacterial infection in patients with cirrhosis who have GI bleeding. One study noted that the 37% incidence of serious bacterial infection was reduced to 10% when treatment with norfloxacin was instituted. Furthermore, it can be argued that all patients with low-protein ascites should undergo prophylactic therapy (eg, with norfloxacin 400 mg/d PO) at the time of hospital admission, given the high incidence of hospital-acquired SBP.
Other complications of massive ascites
Patients with massive ascites may experience abdominal discomfort, depressed appetite, and decreased oral intake. Diaphragmatic elevation may lead to symptoms of dyspnea. Pleural effusions may result from the passage of ascitic fluid across channels in the diaphragm.
Umbilical and inguinal hernias are common in patients with moderate and massive ascites. The use of an elastic abdominal binder may protect the skin overlying a protruding umbilical hernia from maceration and may help prevent rupture and subsequent infection. Timely large-volume paracentesis also may help to prevent this disastrous complication. Umbilical hernias should not undergo elective repair unless patients are significantly symptomatic or their hernias are irreducible. As with all other surgeries in patients with cirrhosis, herniorrhaphy carries multiple potential risks, such as intraoperative bleeding, postoperative infection, and liver failure, because of anesthesia-induced reductions in hepatic blood flow. However, these risks become acceptable in patients with severe symptoms from their hernia. Urgent surgery is necessary in the patient whose hernia has been complicated by bowel incarceration.
Paracentesis in the diagnosis of ascites
Paracentesis is essential in determining whether ascites is caused by portal hypertension or by another process. Ascites studies also are used to rule out infection and malignancy. Paracentesis should be performed in all patients with either new onset of ascites or worsening ascites. Paracentesis also should be performed when SBP is suggested by the presence of abdominal pain, fever, leukocytosis, or worsening hepatic encephalopathy. Some argue that paracentesis should be performed in all patients with cirrhosis who have ascites at the time of hospitalization, given the significant possibility of asymptomatic SBP.
Table 3. Ascites Tests
Routine
Optional
Special
Cell count
Total protein
Cytology
Albumin
Glucose
TB smear and culture
Culture
Lactic dehydrogenase
Triglycerides
Gram stain
Bilirubin
Amylase
Ascitic fluid with more than 250 PMNs/mm3 defines neutrocytic ascites and SBP. Many cases of ascites fluid with more than 1000 PMNs/mm3 (and certainly >5000 PMNs/mm3) are associated with appendicitis or a perforated viscus with resulting bacterial peritonitis. Appropriate radiologic studies must be performed in such patients to rule out surgical causes of peritonitis. Lymphocyte-predominant ascites raises concerns about the possibility of underlying malignancy or tuberculosis. Similarly, grossly bloody ascites may be observed in malignancy and tuberculosis. Bloody ascites is seen infrequently in uncomplicated cirrhosis. A common clinical dilemma is how to interpret the ascites PMN count in the setting of bloody ascites. This author recommends subtraction of 1 PMN for every 250 RBCs in ascites to ascertain a corrected PMN count.
The yield of ascites culture studies may be increased by directly inoculating 10 mL of ascites into aerobic and anaerobic culture bottles at the patient's bedside.
Medical treatment of ascites
Therapy for ascites should be tailored to the patient's needs. Some patients with mild ascites respond to sodium restriction or diuretics taken once or twice per week. Other patients require aggressive diuretic therapy, careful monitoring of electrolytes, and occasional hospitalization to facilitate even more intensive diuresis.
Sodium restriction
Salt restriction is the first line of therapy. In general, patients begin with a diet containing less than 2000 mg sodium per day. Some patients with refractory ascites require a diet containing less than 500 mg sodium per day. However, ensuring that patients do not construct diets that might place them at risk for calorie and protein malnutrition is important. Indeed, the benefit of commercially available liquid nutritional supplements (which often contain moderate amounts of sodium) often exceeds the risk of slightly increasing the patient's salt intake.
Diuretics
Diuretics should be considered the second line of therapy. Spironolactone (Aldactone) blocks the aldosterone receptor at the distal tubule. It is dosed at 50-300 mg once per day. Although the drug has a relatively short half-life, its blockade of the aldosterone receptor lasts for at least 24 hours. Adverse effects of spironolactone include hyperkalemia, gynecomastia, and lactation. Other potassium-sparing diuretics, including amiloride and triamterene, may be used as alternative agents, especially in patients complaining of gynecomastia.
Furosemide (Lasix) may be used as a solo agent or in combination with spironolactone. The drug blocks sodium reuptake in the loop of Henle. It is dosed at 40-240 mg per day in 1-2 divided doses. Patients infrequently need potassium repletion when furosemide is dosed in combination with spironolactone.
Aggressive diuretic therapy in hospitalized patients with massive ascites can safely induce a 0.5- to 1-kg weight loss per day, providing that patients undergo careful monitoring of renal function. Diuretic therapy should be held in the event of electrolyte disturbances, azotemia, or induction of hepatic encephalopathy. Thus far, evidence-based medicine has not firmly supported the use of albumin as an aid to diuresis in the patient with cirrhosis who is hospitalized. The author's anecdotal experience suggests that albumin may increase the efficacy and safety of diuretics. The author's practice in hospitalized patients who are hypoalbuminemic is to administer intravenous furosemide following intravenous infusion of albumin at 25 g twice per day, in addition to ongoing therapy with spironolactone. One recent article supported the use of chronic albumin infusions to achieve diuresis in patients with diuretic-resistant ascites.
Albumin infusion may protect against the development of renal insufficiency in patients with SBP. Patients receiving cefotaxime and albumin at 1 g/kg/day experienced a lower risk of renal failure and a lower in-hospital mortality rate than patients treated with cefotaxime and conventional fluid management.
Satavaptan, a vasopressin V2 receptor antagonist, is a promising new investigational agent that may improve diuresis and decrease the need for paracentesis in patients with diuretic-refractory ascites.
Large-volume paracentesis
Aggressive diuretic therapy is ineffective in controlling ascites in approximately 5-10% of patients. Such patients with massive ascites may need to undergo large-volume paracentesis to receive relief from symptoms of abdominal discomfort, anorexia, or dyspnea. The procedure also may help reduce the risk of umbilical hernia rupture.
Large-volume paracentesis was first used in ancient times. It fell out of favor from the 1950s through the 1980s with the advent of diuretic therapy and following a handful of case reports describing paracentesis-induced azotemia. In 1987, Gines and colleagues demonstrated that large-volume paracentesis could be performed with minimal or no impact on renal function. This and other studies showed that 5-15 L of ascites could be removed safely at one time. Large-volume paracentesis is thought to be safe in patients with peripheral edema and in patients not currently treated with diuretics. Debate exists whether colloid infusions (eg, with 5-10 g albumin per 1 L ascites removed) are necessary to prevent intravascular volume depletion in patients who are receiving ongoing diuretic therapy or in patients with mild or moderate underlying renal insufficiency.
Peritoneovenous shunts
LeVeen shunts and Denver shunts are devices that permit the return of ascites fluid and proteins to the intravascular space. Plastic tubing inserted subcutaneously under local anesthesia connects the peritoneal cavity to the internal jugular vein or subclavian vein via a pumping chamber. These devices are successful at relieving ascites and reversing protein loss in some patients. However, serious complications are observed in 10% of the recipients of these devices. Complications include peritoneal infection, sepsis, disseminated intravascular coagulation, and congestive heart failure. Shunts may clot and require replacement in an additional 30% of patients. However, peritoneovenous shunts may be a reasonable form of therapy for patients with refractory ascites who are not candidates for TIPS or liver transplantation.
Portosystemic shunts and transjugular intrahepatic portosystemic shunts
The prime indication for portocaval shunt surgery is the management of refractory variceal bleeding. However, since 1945, the medical field has recognized that portocaval shunts, by decompressing the hepatic sinusoid, may improve ascites. The performance of a side-to-side portocaval shunt for ascites management must be weighed against the approximate 5% mortality rate associated with this surgery and the chance (as high as 30%) of inducing hepatic encephalopathy.
TIPS is an effective tool in managing massive ascites in some patients. Ideally, TIPS placement produces a decrease in sinusoidal pressure and a decrease in plasma renin and aldosterone levels, with subsequent improved urinary sodium excretion. In one study, 74% of patients with refractory ascites achieved complete remission of ascites within 3 months of TIPS placement. However, patient selection for the procedure is important. Creation of TIPS has the potential to worsen preexisting hepatic encephalopathy and exacerbate liver dysfunction in patients with severe underlying liver failure.
In the author's opinion, TIPS use should be reserved for patients with Child Class B cirrhosis or patients with Child Class C cirrhosis without severe coagulopathy or encephalopathy. Previously, shunt stenosis was observed in one half of cases within 1 year of placement, necessitating angiographic revision. Although the advent of coated stents appears to be reducing the incidence of shunt stenosis, patients must still be willing to return to the hospital for Doppler and angiographic follow-up of TIPS patency.
Liver transplantation
Patients with massive ascites have a less than 50% 1-year survival rate. Liver transplantation should be considered as a potential means of salvaging the patient prior to the onset of intractable liver failure or hepatorenal syndrome.

HEPATIC ENCEPHALOPATHY
Section 6 of 10
Author Information Definition, Epidemiology, And Etiology Of Cirrhosis Pathophysiology Of Hepatic Fibrosis Portal Hypertension Ascites Hepatic Encephalopathy Other Manifestations Of Cirrhosis; Assessment Of Severity Of Cirrhosis Treatment Of Cirrhosis Liver Transplantation Bibliography
Definition
Hepatic encephalopathy is a syndrome observed in some patients with cirrhosis that is marked by personality changes, intellectual impairment, and a depressed level of consciousness. The diversion of portal blood into the systemic circulation appears to be a prerequisite for the syndrome. Indeed, hepatic encephalopathy may develop in patients who do not have cirrhosis who undergo portocaval shunt surgery.
Pathogenesis
A number of theories have been postulated to explain the pathogenesis of hepatic encephalopathy in patients with cirrhosis. Patients may have altered brain energy metabolism and increased permeability of the blood-brain barrier. The latter may facilitate the passage of neurotoxins into the brain. Putative neurotoxins include short-chain fatty acids, mercaptans, false neurotransmitters (eg, tyramine, octopamine, and beta-phenylethanolamines), ammonia, and gamma-aminobutyric acid (GABA).
The ammonia hypothesis
Ammonia is produced in the GI tract by bacterial degradation of amines, amino acids, purines, and urea. Normally, ammonia is detoxified in the liver by conversion to urea and glutamine. In liver disease or portosystemic shunting, portal blood ammonia is not converted efficiently to urea. Increased levels of ammonia may enter the systemic circulation because of portosystemic shunting.
Ammonia has multiple neurotoxic effects, including altering the transit of amino acids, water, and electrolytes across the neuronal membrane. Ammonia also can inhibit the generation of both excitatory and inhibitory postsynaptic potentials. Therapeutic strategies to reduce serum ammonia levels tend to improve hepatic encephalopathy. However, approximately 10% of patients with significant encephalopathy have normal serum ammonia levels. Furthermore, many patients with cirrhosis have elevated ammonia levels without evidence of encephalopathy.
The gamma-aminobutyric acid hypothesis
GABA is a neuroinhibitory substance produced in the GI tract. Until recently, it was postulated that GABA crossed the extrapermeable blood-brain barriers of patients with cirrhosis and then interacted with supersensitive postsynaptic GABA receptors. This would lead to the generation of inhibitory postsynaptic potentials. Clinically, this interaction was believed to produce the symptoms of hepatic encephalopathy. However, recent work suggests that brain GABA levels are not increased in patients with cirrhosis.
Brain levels of neurosteroids are increased in patients with cirrhosis. They are capable of binding to their receptor within the neuronal GABA receptor complex and can increase inhibitory neurotransmission. Today, some investigators contend that neurosteroids may play a key role in hepatic encephalopathy.
Clinical features of hepatic encephalopathy
The symptoms of hepatic encephalopathy may range from mild to severe and may be observed in as many as 70% of patients with cirrhosis. Symptoms are graded on the following scale:
Grade 0 - Subclinical; normal mental status, but minimal changes in memory, concentration, intellectual function, coordination
Grade 1 - Mild confusion, euphoria or depression, decreased attention, slowing of ability to perform mental tasks, irritability, disorder of sleep pattern (ie, inverted sleep cycle)
Grade 2 - Drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behavior, intermittent disorientation (usually for time)
Grade 3 - Somnolent but arousable, unable to perform mental tasks, disorientation to time and place, marked confusion, amnesia, occasional fits of rage, speech is present but incomprehensible
Grade 4 - Coma, with or without response to painful stimuli
Patients with mild and moderate hepatic encephalopathy demonstrate decreased short-term memory and concentration on mental status testing. Findings upon physical examination include asterixis and fetor hepaticus.
Laboratory abnormalities in hepatic encephalopathy
An elevated arterial or free venous serum ammonia level is the classic laboratory abnormality reported in patients with hepatic encephalopathy. This finding may aid in the assignment of a correct diagnosis to a patient with cirrhosis who presents with altered mental status. However, serial ammonia measurements are inferior to clinical assessment in gauging improvement or deterioration in patients under therapy for hepatic encephalopathy. No utility exists for checking the ammonia level in a patient with cirrhosis who does not have hepatic encephalopathy.
Some patients with hepatic encephalopathy have the classic but nonspecific electroencephalogram (EEG) changes of high-amplitude low-frequency waves and triphasic waves. EEG may be helpful in the initial workup of a patient with cirrhosis and altered mental status when ruling out seizure activity may be necessary.
CT scan and MRI studies of the brain may be important in ruling out intracranial lesions when the diagnosis of hepatic encephalopathy is in question.
Common precipitants of hepatic encephalopathy
Some patients with a history of hepatic encephalopathy may have normal mental status when under medical therapy. Others have chronic memory impairment in spite of medical management. Both groups of patients are subject to episodes of worsened encephalopathy. Common precipitants of hyperammonemia and worsening mental status are diuretic therapy, renal failure, GI bleeding, infection, and constipation. Dietary protein overload is an infrequent cause of worsening encephalopathy. Medications, notably opiates, benzodiazepines, antidepressants, and antipsychotic agents, also may worsen encephalopathy symptoms.
Differential diagnosis for hepatic encephalopathy
Conditions in the differential diagnosis of encephalopathy include the following:
Intracranial lesions (eg, subdural hematoma, intracranial bleeding, cerebrovascular accident, tumor, abscess)
Infections (eg, meningitis, encephalitis, abscess)
Metabolic encephalopathy (eg, hypoglycemia, electrolyte imbalance, anoxia, hypercarbia, uremia)
Hyperammonemia from other causes (eg, secondary to ureterosigmoidostomy, inherited urea cycle disorders)
Toxic encephalopathy due to alcohol (eg, acute intoxication, alcohol withdrawal, Wernicke encephalopathy)
Toxic encephalopathy due to drugs (eg, sedative-hypnotics, antidepressants, antipsychotic agents, salicylates)
Organic brain syndrome
Postseizure encephalopathy
Management of hepatic encephalopathy
Nonhepatic causes of altered mental function must be excluded in patients with cirrhosis who have worsening mental function. A check of the blood ammonia level may be helpful in such patients. Medications that depress CNS function, especially benzodiazepines, should be avoided. Precipitants of hepatic encephalopathy should be corrected (eg, metabolic disturbances, GI bleeding, infection, constipation).
Lactulose is helpful in patients with the acute onset of severe encephalopathy symptoms and in patients with milder, chronic symptoms. This nonabsorbable disaccharide stimulates the passage of ammonia from tissues into the gut lumen and inhibits intestinal ammonia production. Initial lactulose dosing is 30 mL orally once or twice daily. Dosing is increased until the patient has 2-4 loose stools per day. Dosing should be reduced if the patient complains of diarrhea, abdominal cramping, or bloating. Higher doses of lactulose may be administered via either a nasogastric tube or rectal tube to hospitalized patients with severe encephalopathy. Other cathartics, including colonic lavage solutions that contain polyethylene glycol (PEG) (eg, Go-Lytely), also may be effective in patients with severe encephalopathy.
Neomycin and other antibiotics (eg, metronidazole, oral vancomycin, paromomycin, oral quinolones) serve as second-line agents. They work by decreasing the colonic concentration of ammoniagenic bacteria. Neomycin dosing is 250-1000 mg orally 2-4 times daily. Treatment with neomycin may be complicated by ototoxicity and nephrotoxicity.
Rifaximin (Xifaxan, Salix Pharmaceuticals, Inc, Morrisville, NC) is a nonabsorbable antibiotic that received approval by the US Food and Drug Administration (FDA) in 2004 for the treatment of travelers' diarrhea. Experience in Europe over the last 2 decades suggests that rifaximin can decrease colonic levels of ammoniagenic bacteria, with resulting improvement in hepatic encephalopathy symptoms. Typical rifaximin dosing in European hepatic encephalopathy trials was two 200 mg tablets taken orally 3 times daily. Work is being done to determine if lower doses of the medication can effectively treat hepatic encephalopathy.
Other chemicals capable of decreasing blood ammonia levels are L-ornithine L-aspartate (available in Europe) and sodium benzoate.
Low-protein diets were recommended routinely in the past for patients with cirrhosis. High levels of aromatic amino acids contained in animal proteins were believed to lead to increased blood levels of the false neurotransmitters tyramine and octopamine, with resulting worsening of encephalopathy symptoms. In this author's experience, the vast majority of patients can tolerate a protein-rich diet (>1.2 g/kg/d) including well-cooked chicken, fish, vegetable protein, and, if needed, protein supplements. Although protein restriction may play a role in the management of the patient with an acute flare of hepatic encephalopathy, it rarely is necessary in patients with chronic encephalopathy symptoms. Furthermore, many patients with cirrhosis have protein-calorie malnutrition at baseline. The routine restriction of dietary protein intake increases their risk for worsening malnutrition.

OTHER MANIFESTATIONS OF CIRRHOSIS; ASSESSMENT OF SEVERITY OF CIRRHOSIS
Section 7 of 10
Author Information Definition, Epidemiology, And Etiology Of Cirrhosis Pathophysiology Of Hepatic Fibrosis Portal Hypertension Ascites Hepatic Encephalopathy Other Manifestations Of Cirrhosis; Assessment Of Severity Of Cirrhosis Treatment Of Cirrhosis Liver Transplantation Bibliography
All chronic liver diseases that progress to cirrhosis have in common the histologic features of hepatic fibrosis and nodular regeneration. However, patients' signs and symptoms may vary depending on the underlying etiology of liver disease. As an example, patients with end-stage liver disease caused by hepatitis C might develop profound muscle wasting, marked ascites, and severe hepatic encephalopathy, with only mild jaundice. In contrast, patients with end-stage primary biliary cirrhosis might be deeply icteric, with no evidence of muscle wasting. These patients may complain of extreme fatigue and pruritus and have no complications of portal hypertension. In both cases, medical management is focused on the relief of symptoms. Liver transplantation should be considered as a potential therapeutic option, given the inexorable course of most cases of end-stage liver disease.
Many patients with cirrhosis experience fatigue, anorexia, weight loss, and muscle wasting. Cutaneous manifestations of cirrhosis include jaundice, spider angiomata, skin telangiectasias (termed “paper money skin” by Dame Sheila Sherlock), palmar erythema, white nails, disappearance of lunulae, and finger clubbing, especially in the setting of hepatopulmonary syndrome.
Patients with cirrhosis may experience increased conversion of androgenic steroids into estrogens in skin, adipose tissue, muscle, and bone. Males may develop gynecomastia and impotence. Loss of axillary and pubic hair is noted in both men and women. Hyperestrogenemia also may explain spider angiomata and palmar erythema.
Hematologic manifestations
Anemia may result from folate deficiency, hemolysis, or hypersplenism. Thrombocytopenia usually is secondary to hypersplenism and decreased levels of thrombopoietin. Coagulopathy results from decreased hepatic production of coagulation factors. If cholestasis is present, decreased micelle entry into the small intestine leads to decreased vitamin K absorption, with resulting reduction in hepatic production of factors II, VII, IX, and X. Patients with cirrhosis also may experience fibrinolysis and disseminated intravascular coagulation.
Pulmonary and cardiac manifestations
Patients with cirrhosis may have impaired pulmonary function. Pleural effusions and the diaphragmatic elevation caused by massive ascites may alter ventilation-perfusion relations. Interstitial edema or dilated precapillary pulmonary vessels may reduce pulmonary diffusing capacity.
Patients also may have hepatopulmonary syndrome (HPS). In this condition, pulmonary arteriovenous anastomoses result in arteriovenous shunting. HPS is a potentially progressive and life-threatening complication of cirrhosis. Classic HPS is marked by the symptom of platypnea and the finding of orthodeoxia, but the syndrome must be considered in any patient with cirrhosis who has evidence of oxygen desaturation. HPS is detected most readily by echocardiographic visualization of late-appearing bubbles in the left atrium following the injection of agitated saline. Patients can receive a diagnosis of HPS when their PaO2 is less than 70 mm Hg. Some cases of HPS may be corrected by liver transplantation. In fact, patients may receive an expedited course to liver transplantation when their PaO2 is less than 60 mm Hg.
Portopulmonary hypertension (PPHTN) is observed in up to 6% of patients with cirrhosis. Its etiology is unknown. PPHTN is defined as the presence of a mean pulmonary artery pressure of greater than 25 mm Hg in the setting of a normal pulmonary capillary wedge pressure. Routine Doppler echocardiography is performed as part of many liver transplant programs to rule out the interval development of PPHTN in patients on the transplant waiting list. Indeed, the presence of a mean pulmonary pressure of greater than 35 mm Hg significantly increases the risks of liver transplant surgery. Patients who develop severe PPHTN may require aggressive medical therapy in an effort to stabilize pulmonary artery pressures and to decrease their chance of perioperative mortality.
Hepatocellular carcinoma and cholangiocarcinoma
Hepatocellular carcinoma (HCC) occurs in 10-25% of patients with cirrhosis in the United States and most often is associated with hemochromatosis, alpha-1 antitrypsin deficiency, hepatitis B, hepatitis C, and alcoholic cirrhosis. HCC is observed less commonly in primary biliary cirrhosis and is a rare complication of Wilson disease. Cholangiocarcinoma occurs in approximately 10% of patients with primary sclerosing cholangitis.
Other diseases associated with cirrhosis
Other conditions that appear with increased incidence in patients with cirrhosis include peptic ulcer disease, diabetes, and gallstones.
Assessment of the severity of cirrhosis
The most common tool for gauging prognosis in cirrhosis is the Child-Turcotte-Pugh (CTP) system. Child and Turcotte first introduced their scoring system in 1964 as a means of predicting the operative mortality associated with portocaval shunt surgery. Pugh's revised system in 1973 substituted albumin for the less specific variable of nutritional status. More recent revisions use the International Normalized Ratio (INR) in addition to prothrombin time.
Recent epidemiologic work shows that the CTP score may predict life expectancy in patients with advanced cirrhosis. A CTP score of 10 or greater is associated with a 50% chance of death within 1 year.
Since 2002, liver transplant programs in the United States have used the Model for End-Stage Liver Disease (MELD) scoring system to assess the relative severities of patients' liver diseases (see Liver Transplantation). Patients may receive a MELD score of 6-40 points. The 3-month mortality statistics are associated with the following MELD scores: MELD score of less than 9, 2.9% mortality; MELD score of 10-19, 7.7% mortality; MELD score of 20-29, 23.5% mortality; MELD score of 30-39, 60% mortality; and MELD score of greater than 40, 81% mortality.
Table 4. Child-Turcotte-Pugh Scoring System for Cirrhosis (Child Class A=5-6 points, Child Class B=7-9 points, Child Class C=10-15 points)
Clinical variable
1 points
2 points
3 points
Encephalopathy
None
Stage 1-2
Stage 3-4
Ascites
Absent
Slight
Moderate
Bilirubin (mg/dL)
<2
2-3
>3
Bilirubin in PBC orPSC (mg/dL)
<4
4-10
10
Albumin (g/dL)
>3.5
2.8-3.5
<2.8
Prothrombin time(seconds prolongedor INR)
<4 s orINR <1.7
4-6 s orINR 1.7-2.3
>6 s orINR >2.3
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TREATMENT OF CIRRHOSIS
Section 8 of 10
Author Information Definition, Epidemiology, And Etiology Of Cirrhosis Pathophysiology Of Hepatic Fibrosis Portal Hypertension Ascites Hepatic Encephalopathy Other Manifestations Of Cirrhosis; Assessment Of Severity Of Cirrhosis Treatment Of Cirrhosis Liver Transplantation Bibliography
Specific medical therapies may be applied to many liver diseases in an effort to diminish symptoms and to prevent or forestall the development of cirrhosis. Examples include prednisone and azathioprine for autoimmune hepatitis, interferon and other antiviral agents for hepatitis B and C, phlebotomy for hemochromatosis, ursodeoxycholic acid for primary biliary cirrhosis, and trientine and zinc for Wilson disease. These therapies become progressively less effective if chronic liver disease evolves into cirrhosis. Once cirrhosis develops, treatment is aimed at the management of complications as they arise. Certainly variceal bleeding, ascites, and hepatic encephalopathy are among the most serious complications experienced by patients with cirrhosis. However, attention also must be paid to patients' chronic constitutional complaints.
Nutrition
Many patients complain of anorexia, which may be compounded by the direct compression of ascites on the GI tract. Care should be taken to ensure that patients receive adequate calories and protein in their diets. Patients frequently benefit from the addition of commonly available liquid and powdered nutritional supplements to the diet. Only rarely can patients not tolerate proteins in the form of chicken, fish, vegetables, and nutritional supplements. Institution of a low-protein diet in the fear that hepatic encephalopathy might develop places the patient at risk for the development of profound muscle wasting.
Adjunctive therapies
Zinc deficiency commonly is observed in patients with cirrhosis. Treatment with zinc sulfate at 220 mg orally twice daily may improve dysgeusia and can stimulate appetite. Furthermore, zinc is effective in the treatment of muscle cramps and is adjunctive therapy for hepatic encephalopathy.
Pruritus is a common complaint in both cholestatic liver diseases (eg, primary biliary cirrhosis) and in noncholestatic chronic liver diseases (eg, hepatitis C). Although increased serum bile acid levels once were thought to be the cause of pruritus, endogenous opioids are more likely to be the culprit pruritogens. Mild itching complaints may respond to treatment with antihistamines.
Cholestyramine is the mainstay of therapy for the pruritus of liver disease. Care should be taken to avoid coadministration of this organic anion binder with any other medication, to avoid compromising GI absorption. Other medications that may provide relief against pruritus include ursodeoxycholic acid, ammonium lactate 12% skin cream (Lac-Hydrin, Westwood-Squibb Pharmaceuticals, Inc, Princeton, NJ), naltrexone (an opioid antagonist), rifampin, gabapentin, and ondansetron. Patients with severe pruritus may require institution of ultraviolet light therapy or plasmapheresis.
Some male patients suffer from hypogonadism. Patients with severe symptoms may undergo therapy with topical testosterone preparations, although their safety and efficacy is not well studied. Similarly, the utility and safety of growth hormone therapy remains unclear.
Patients with cirrhosis may develop osteoporosis. Supplementation with calcium and vitamin D is important in patients at high risk for osteoporosis, especially patients with chronic cholestasis, patients with primary biliary cirrhosis, and patients receiving corticosteroids for autoimmune hepatitis. The discovery of decreased bone mineralization upon bone densitometry studies also may prompt institution of therapy with an aminobisphosphonate (eg, alendronate sodium).
Regular exercise, including walking and even swimming, should be encouraged in patients with cirrhosis, lest the patient slip into a vicious cycle of inactivity and muscle wasting. Debilitated patients frequently benefit from formal exercise programs supervised by a physical therapist. Patients with chronic liver disease should receive vaccination to protect them against hepatitis A. Other protective measures include vaccination against hepatitis B, pneumococci, and influenza.
Drug hepatotoxicity in the patient with cirrhosis
The institution of any new medical therapy warrants the performance of more frequent liver chemistries. Indeed, patients with liver disease can ill afford to have drug-induced liver disease superimposed on their condition. Medications associated with drug-induced liver disease include NSAIDs, isoniazid, valproic acid, erythromycin, amoxicillin/clavulanate, ketoconazole, and chlorpromazine and ezetimibe.
Hepatic 3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitors are frequently associated with mild elevations of alanine aminotransferase (ALT) levels. However, severe hepatotoxicity is reported infrequently. Recent literature suggests that statins can be used safely in most patients with chronic liver disease. Certainly, liver chemistries should be followed frequently after the initiation of therapy.
NSAID use may predispose patients with cirrhosis to develop GI bleeding. Patients with decompensated cirrhosis are at risk for NSAID-induced renal insufficiency, presumably because of prostaglandin inhibition and worsening of renal blood flow. Other nephrotoxic agents, such as aminoglycoside antibiotics, also should be avoided.
Low-dose estrogens and progesterone appear to be safe in the setting of liver disease.
Surgery in the patient with cirrhosis
Surgery and general anesthesia carry increased risks in the patient with cirrhosis. Anesthesia reduces cardiac output, induces splanchnic vasodilation, and causes a 30- to 50%-reduction in hepatic blood flow. This places the cirrhotic liver at additional risk for decompensation. Surgery is said to be safe in the setting of mild chronic hepatitis. Its risk in patients with severe chronic hepatitis is unknown. Patients with well-compensated cirrhosis have an increased but acceptable risk of morbidity and mortality. A study of nonshunt abdominal surgeries demonstrated a 10% mortality rate for patients with Child Class A cirrhosis as opposed to a 30% mortality rate for patients with Child Class B cirrhosis and a 75% mortality rate for patients with Child Class C cirrhosis. Thus, unless absolutely necessary, surgery should be avoided in the patient with cirrhosis. Although cholecystectomy was among the riskier surgeries noted, several recent reports have described the successful performance of laparoscopic cholecystectomy in patients with Child Class A and B cirrhosis.
Monitoring the patient with cirrhosis
Patients with cirrhosis should undergo routine follow-up monitoring of their complete blood count, renal and liver chemistries, and prothrombin time. The author's policy is to monitor stable patients 3-4 times per year. The author performs routine diagnostic endoscopy to determine whether the patient has asymptomatic esophageal varices. Follow-up endoscopy is performed in 2 years if varices are not present. If varices are present, treatment is initiated with a nonselective beta-blocker (eg, propranolol, nadolol), aiming for a 25% reduction in heart rate. Such therapy offers effective primary prophylaxis against the new onset of variceal bleeding. Patients intolerant of beta-blockers should undergo prophylactic endoscopic variceal ligation.
This author encourages the screening of patients to rule out the interval development of HCC. The author's practice is to perform abdominal ultrasonography and alpha-fetoprotein testing twice yearly, although the clinical utility and cost-effectiveness of this strategy remains controversial. In the past, clinical suspicion for HCC mandated the performance of a confirmatory biopsy, by either ultrasound or CT guidance. However, guided biopsy is accompanied by a significant false-negative rate. Biopsy may be complicated either by hemorrhage or by the tracking of tumor cells in the needle tract. Increasingly, patients with clinical diagnoses of cirrhosis and HCC are monitored in the setting of liver transplant programs. Many hepatologists and surgeons now rely on noninvasive testing when it comes to making a diagnosis of HCC. In most transplant programs, the presence of a suspicious lesion on both triple-phase CT scan and MRI or the combination of a suspicious finding on radiologic study and an alpha-fetoprotein (AFP) level of greater than 400 ng/mL is believed to have the same or an even greater diagnostic power than guided liver biopsy.
Patients with a diagnosis of HCC and no evidence of extrahepatic disease, as determined by chest and abdominal CT scans and by bone scan, should be offered curative therapy. Commonly, this therapy entails liver resection surgery for patients with Child Class A cirrhosis and an accelerated course to liver transplantation for patients with Child Class B and C cirrhosis. Patients who await liver transplantation are often offered minimally invasive therapies in an effort to keep tumors from spreading. These therapies include percutaneous injection therapy with ethanol, radiofrequency thermal ablation, and chemoembolization.
Patient education
For excellent patient education resources, visit eMedicine's Mental Health and Behavior Center. Also, see eMedicine's patient education article Alcoholism.

LIVER TRANSPLANTATION
Section 9 of 10
Author Information Definition, Epidemiology, And Etiology Of Cirrhosis Pathophysiology Of Hepatic Fibrosis Portal Hypertension Ascites Hepatic Encephalopathy Other Manifestations Of Cirrhosis; Assessment Of Severity Of Cirrhosis Treatment Of Cirrhosis Liver Transplantation Bibliography
Liver transplantation has emerged as an important strategy in the management of patients with decompensated cirrhosis. Patients should be referred for consideration of liver transplantation after the first signs of hepatic decompensation.
Advances in surgical technique, organ preservation, and immunosuppression have resulted in dramatic improvements in postoperative survival over the last 2 decades. In the early 1980s, the percentage of patients surviving 1 year and 5 years after liver transplant were only 70% and 15%, respectively. Now, patients can anticipate a 1-year survival rate of 85-90% and a 5-year survival rate of higher than 70%. Quality of life after liver transplant is good or excellent in most cases.
Contraindications for liver transplantation include severe cardiovascular or pulmonary disease, active drug or alcohol abuse, malignancy outside the liver, sepsis, or psychosocial problems that might jeopardize patients' abilities to follow their medical regimens after transplant. The presence of HIV in the bloodstream also is a contraindication to transplant. However, successful liver transplantations are now being performed in patients with no detectable HIV viral load due to antiretroviral therapy. Additional clinical study is required before liver transplantation can be offered routinely to such patients.
Organ allocation
Approximately 5000 liver transplants are performed in the United States each year. An increasing number of lives are saved each year by transplant. However, the number of diagnosed cases of cirrhosis is rising, fueled in part by the hepatitis C epidemic and by the growing number of cases of NAFLD. This has resulted in a dramatic increase in the number of patients listed as candidates for liver transplantation.
Approximately 12-15% of patients listed as candidates die while waiting because of the relatively static number of organ donations. Strategies to improve the current donor organ shortage include programs to increase public awareness of the importance of organ donation, increased use of living donor liver transplantation for pediatric and adult recipients, organ donation after cardiac death, and the use of extended criteria donors (ECD).
In ECD, the donor "deviates in some aspect from the ideal donor." One example of an ECD organ is the hepatitis C-infected liver with minimal fibrosis that is transplanted into an HCV-infected recipient. Such transplants have been performed successfully for a number of years. Other examples of extended criteria donors include donors older than 70 years, donors with relatively fatty livers, and donors infected with HTLV-I or HTLV-II.
The need for a more efficient and equitable system of organ allocation resulted in dramatic changes in United States organ allocation policy in 2002. Previously, patients who were accepted as liver transplant candidates with 7-9 CTP points (Child Class B) received low priority on the transplant waiting list maintained by the United Network for Organ Sharing (UNOS). Patients with 10 or more CTP points (Child Class C) received a higher priority. Emergent liver transplantation at the UNOS Status 1 was reserved primarily for noncirrhotic patients suffering from fulminant hepatic failure.
Since 2002, livers from deceased donors (ie, cadaveric organs) have been allocated to cirrhotic patients using the MELD scoring system and the Pediatric End-Stage Liver Disease (PELD) scoring system.
In the MELD scoring system for adults, a patient receives a score based upon the following formula: MELD score = 0.957 x Loge(creatinine mg/dL) + 0.378 x Loge(bilirubin mg/dL) + 1.120 x Loge(INR) + 0.643. As an example, a cirrhotic patient with a creatinine of 1.9 mg/dL, a bilirubin of 4.2 mg/dL, and an INR of 1.2 receives the following score: MELD score = (0.957 x Loge1.9) + (0.378 x Loge4.2) + (1.120 x Loge1.2) + 0.643 = 2.039. That value is then multiplied by 10 to give the patient a risk score of 20. Patients' MELD scores are recalculated every time they undergo laboratory testing. Patients may be assigned a maximum MELD score of 40 points.
The PELD system uses a somewhat different formula: PELD score = 0.480 x Loge(total bilirubin mg/dL) + 1.857 x Loge(INR) - 0.687 x Loge(albumin g/dL) + 0.436 if the patient is younger than 1 year + 0.667 if the patient has growth failure (<2 standard deviations). This value is multiplied by 10 to give a final risk score.
Within any region of the country, a donor organ in a particular ABO blood group is allocated to the cirrhotic patient within the same blood group who has the highest MELD or PELD score. Special rules have been developed to address potentially life-threatening liver disease complications, such as hepatocellular carcinoma and hepatopulmonary syndrome. Patients with these conditions, as well as other exceptional cases, can receive a higher MELD or PELD score than that calculated from creatinine, bilirubin, and INR alone.
Living donor liver transplantation
The advent of living donor liver transplantation (LDLT) has introduced a new variable into any discussion of the timing of transplantation. LDLT has the potential to make liver transplantation an elective procedure not only for the cirrhotic patient with significant complications but also for the cirrhotic patient with a poor quality of life. LDLT became a reality for pediatric recipients in 1988 and for adult recipients a decade later. The procedure arose from both advances in surgical technique and a worsening shortage of deceased donor organs. In LDLT, up to 60% of a healthy volunteer donor's liver can be surgically resected and transplanted into the abdomen of a needful recipient. Graft survival in LDLT recipients is on par with that seen in the recipients of deceased donor organs.
However, LDLT has its limitations. The most obvious problem is the low, but real, risk of serious operative complications for the healthy volunteer liver donor. It is estimated that about 0.4% of the more than 3000 healthy liver donors worldwide over the last decade have died as a consequence of their surgery. Thus, transplant programs must maximize donor safety. They must also ensure that the benefits of LDLT to the potential recipient offset the risks to the donor. Furthermore, not every potential recipient is sufficiently stable to undergo safe and effective LDLT. Indeed, the recipient's risk of posttransplant mortality increases when his or her MELD score is greater than 25. In the author's opinion, LDLT should not be performed in such recipients.
The future of liver transplantation
Exciting new technical advances also may help to improve patients' chances of survival. In the future, expanded use of hepatocyte transplantation may occur. In this therapy, a splenic artery catheter is used to deliver billions of cryopreserved hepatocytes into the spleen of a patient who has end-stage liver disease. The patient then undergoes routine immunosuppression. This strategy has been employed successfully in a small number of patients with cirrhosis and FHF who were not candidates for liver transplant surgery.
Bioartificial livers may see increased application in the care of patients with FHF and, perhaps, cirrhosis. The two most studied devices are comprised of semipermeable capillary hollow fiber membranes enclosed in a plastic shell. Either human C3A hepatoma cells or pig hepatocytes are attached to the exterior surface of the membranes as blood from the patient is pumped through the device. Intracranial pressure and hepatic encephalopathy improved in some of the patients with FHF who were assisted with these devices. However, currently available bioartificial livers have not yet fulfilled the goals of biotransforming and removing toxins while supplying the patient with clotting factors and growth factors.
Xenotransplantation may come into fruition during the next decade. To date, all attempts at xenotransplantation in humans have suffered from severe early humoral or late cellular rejection and have resulted in patient death. Advances in genetic engineering may lead to the development of swine whose livers are more likely to undergo graft acceptance when transplanted into humans. Once this obstacle is overcome, a determination may be made whether a swine liver is an effective substitute for a human liver.
Most importantly, the medical world awaits the development of medical therapies that forestall the development of hepatic fibrosis long before patients develop cirrhosis and its complications.

BIBLIOGRAPHY
Section 10 of 10
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biliary disease

2007-12-08T05:48:00.000-08:00

Pathophysiology: Bile is produced by the liver and channeled by the biliary ductal system into the intestinal tract for the emulsification and absorption of fats. Biliary disease is caused by abnormalities in bile composition, biliary anatomy, or function. The liver determines the chemical composition of bile, and this may be modified later by the gallbladder and biliary epithelium. Cholesterol, ordinarily insoluble in water, comes into solution by forming vesicles with phospholipids (principally lecithin) or mixed micelles with bile salts and phospholipids.
When the ratio of cholesterol, phospholipids, and bile salts is outside an optimum range, cholesterol monohydrate crystals may come out of solution from multilamellar vesicles. Cholesterol supersaturation of bile appears to be a prerequisite for gallstone formation, which involves a variety of factors that affect the activity of low-density lipoprotein (LDL) uptake, hepatic 3-methylglutaryl coenzyme A reductase (HMG CoA), acyl cholesterol-lecithin acyltransferase, and 7-alpha hydroxylase.
By itself, cholesterol supersaturation is inadequate for explaining gallstone pathogenesis. Nucleation, the initial step in gallstone formation, is the transition of cholesterol from a soluble state into a solid crystalline form. Within gallbladder bile, biologic molecules influence the process in a positive or negative fashion.
For example, mucus may function to promote nucleation, while bile-specific glycoproteins may function to inhibit nucleation. Mucin hypersecretion by the gallbladder mucosa creates a viscoelastic gel that fosters nucleation. Arachidonyl lecithin, which is absorbed from the alimentary tract and secreted into the bile, stimulates prostanoid synthesis by gallbladder mucosa and promotes mucus hypersecretion, while inhibitors of prostaglandin inhibit mucus secretion.
Finally, gallbladder hypomotility and bile stasis appear to promote gallstone formation and growth, which may be important in diabetes, pregnancy, oral contraceptive use in women, and prolonged fasting in critically ill patients on total parenteral nutrition.
Frequency:
In the US: Gallstone disease is one of the most common and costly of all digestive diseases. The third National Health and Nutrition Examination Survey estimated that, in the United States, 6.3 million men and 14.2 million women aged 20-74 years had gallbladder disease.
The incidence of gallstones is 1 million new cases per year. The prevalence is 20 million cases among Americans.
Approximately 2-7 cases per 100,000 population of primary sclerosing cholangitis (PSC) exist. About 5% of patients with chronic ulcerative colitis develop PSC.
The incidence of gallbladder cancer is 2.5 cases per 100,000 population.
Internationally: The incidence of primary biliary cirrhosis (PBC) is 5.8-15 cases per 1 million population. The incidence of PBC appears to be increasing, but the cause of the increase is unclear. However, the increase is possibly due to better detection and increased awareness rather than a true change in disease incidence.
Mortality/Morbidity:
Gallstones are a rare cause of mortality, accounting for 5000 of the 2.2 million deaths annually in the United States.
PBC accounts for 0.6-2% of deaths from cirrhosis worldwide. The median time of patient survival was 9.3 years from diagnosis. Independent predictors of survival included age and alkaline phosphatase, serum albumin, and bilirubin levels. Liver failure developed in 26% of patients by 10 years after diagnosis. Neither the presence of antimitochondrial antibodies nor their titer affects disease progression or survival.
PSC is a leading reason for liver transplantation. Median survival without liver transplantation after diagnosis is approximately 12 years. Variables that appear to predict prognosis in PSC include age, histological stage, hepatomegaly, splenomegaly, and serum alkaline phosphatase and serum bilirubin levels.
Race: Mexican Americans and several American Indian tribes, particularly the Pima Indians in the Southwest, have very high prevalence rates of cholesterol gallstones. Decreased bile acid secretion is believed to be the common denominator in these ethnic groups.
Gallbladder cancer is the most common GI malignancy in both Southwestern Native Americans and Mexican Americans. A prominent geographic variability exists in the incidence of gallbladder cancer that correlates with the prevalence of cholelithiasis. High rates of gallbladder cancer are also seen in South American countries, particularly Chile and Bolivia. These populations all share a high prevalence of gallstones and/or Salmonella infection, both recognized risk factors for gallbladder cancer.
Sex: The prevalence of cholesterol gallstones is higher among females than males (lifetime risk of 35% vs 20%, respectively). This likely is due to endogenous sex hormones, which enhance cholesterol secretion and increase bile cholesterol saturation. Progesterone also may contribute by relaxing smooth muscle and impairing gallbladder emptying.
PSC: Males are affected twice as frequently as females.
PBC: Females are affected 9 times as often as males.
Age: Increased age is associated with lithogenic bile and an increased rate of gallstones.
PSC: Mean age of onset is 40 years.
PBC: Among the autoimmune diseases, PBC is unique in that it never occurs in childhood and is rarely found before age 30 years. The onset is usually between the ages of 30-65 years, but the disease has been reported in women as young as 22 years and as old as 93 years.
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CLINICAL
Section 3 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography
History: Biliary disease presents with some diversity, from no symptoms to a constellation of signs and symptoms of varying severity and combination. Accurate diagnosis, therefore, begins with listening closely to the patient. Reaching an accurate diagnosis is aided by clinical experience and often involves imaging studies.
When abdominal pain is the chief symptom, seek to determine when it began and the subsequent events. Clarify what the pain feels like to the patient; visceral pain is perceived as a vague, dull, gnawing, burning, or aching sensation, whereas parietal pain is sharper in quality and better localized. Psychological conditions (eg, anxiety, worry) may enhance pain perception, while impaired consciousness tends to blunt pain perception.
Biliary-type pain: Biliary disease often presents with upper abdominal pain. The pain quality is a penetrating aching or tightness, typically severe and located in the epigastrium. The sensation usually is difficult to describe; it may develop suddenly, last for 15 minutes to several hours, and then resolve suddenly. Although the term biliary colic is used commonly, it is a misnomer because the pattern of pain is constant. The pain is caused by an obstruction to the flow of bile, with distension of the biliary lumen, and is clinically similar whether the obstruction occurs at the cystic duct or at another level of the common bile duct. As noxious visceral stimuli become more intense, referred pain may be experienced in the posterior scapula or right shoulder area and be accompanied by nausea and vomiting.
Jaundice: Bilirubin metabolism and transport principally are handled by the hepatobiliary tract. A yellow discoloration of the skin begins to appear when serum bilirubin rises above 3 mg/dL, and the yellow discoloration is termed jaundice. Abnormalities leading to jaundice may occur in various phases of the process.
Jaundice and abdominal pain: The combination of jaundice and abdominal pain suggests a subacute obstruction of the biliary ductal system. In elderly patients, however, biliary tract obstruction may be painless. Rarely, acute viral hepatitis can be confused with biliary-type pain.
Painless jaundice: The development of jaundice in the absence of abdominal pain is suggestive of a malignant obstruction of the bile duct. Here, the onset of jaundice is gradual and may be associated with anorexia; weight loss; and acholic, soft or loose stools. Nonbiliary causes should be considered, including increased bilirubin production (eg, from hemolysis, blood transfusions, or ineffective erythropoieses) and decreased bilirubin clearance due to hereditary defects (eg, unconjugated hyperbilirubinemia in Gilbert syndrome and Crigler-Najjar syndrome types I and II, conjugated hyperbilirubinemia in Dubin-Johnson syndrome and Rotor syndrome).
Pruritus: Itching is an unpleasant sensation in the skin associated with a strong desire to scratch. While several causes exist, itching is associated with cholestasis and may become the patient's most bothersome symptom. Itching may appear first in the hands and feet* but usually becomes generalized and typically is worse at night. Itching does not distinguish the cause of cholestasis as hepatic or biliary.
Fatigue: The insidious onset of fatigue, followed by pruritus and then jaundice, is observed to varying degrees in diseases of the intrahepatic bile ducts, such as primary biliary cirrhosis, primary sclerosing cholangitis, and vanishing bile duct syndrome.
Weight loss: A history of weight loss is associated with more serious diseases of the biliary tract. The weight loss may be caused by inadequate nutrient intake (eg, anorexia) or malabsorption of fats (eg, a paucity of bile in cholestatic diseases or prolonged biliary obstruction).
Miscellaneous: Other symptoms, including fatty food intolerance, gas, bloating, and dyspepsia, do not indicate the presence of biliary tract disease reliably.
Physical: The patient with acute biliary-type pain often is restless, anxious, and frustrated by unsuccessful attempts to find a comfortable position. Severe pain of acute onset usually is associated with facial grimacing. Writhing, diaphoretic patients usually are acutely and seriously ill; however, some patients with peritonitis may lie still, with a worried facial expression, and avoid being touched or jostled.
Vital signs may be normal. The presence of fever suggests the presence of inflammation or infection. Tachycardia and hypertension occasionally accompany pain. Tachycardia and hypotension suggests hypovolemia or the presence of sepsis.
Skin: In people with light skin color, the skin color may suggest not only jaundice but also provide clues to the etiology; a yellow discoloration is associated with indirect hyperbilirubinemia, a more orange hue can be observed with hepatocellular jaundice, and a dark green tint may develop with prolonged biliary obstruction. Evidence of easy bruisability may indicate a coagulopathy associated with cirrhosis. Patients with cholestasis classically exhibit excoriation of the skin (from scratching, typically sparing the mid back), melanin pigmentation, and xanthomas of the eyelids and extensor surfaces.
Scleral icterus: A yellow discoloration of the whites of the eyes results from hyperbilirubinemia. Although this term is in common use, it actually is a misnomer. The sclerae are relatively impervious to most compounds; the covering conjunctiva becomes permeated with unconjugated bilirubin, causing the yellow appearance. Approximately 58% of examiners are able to detect scleral icterus when the serum bilirubin rises above 2.5 mg/dL.
Abdomen: The abdomen should first be observed to determine if it is scaphoid, flat, distended, or asymmetric. Auscultation may reveal absent bowel sounds, suggesting an ileus, hyperactive bowel sounds (borborygmi), or high-pitched tinkling suggesting intestinal obstruction. The elicitation of pain and involuntary guarding during gentle palpation or jostling of the abdomen suggests peritonitis. Palpation may reveal a mass or fullness in the right upper quadrant.
In the patient with jaundice, an enlarged gallbladder (hydrops) is suggestive of malignant obstruction of the bile duct. In the absence of jaundice, the patient with a palpable mass in the right upper quadrant may have a gallbladder tumor or chronic obstruction of the cystic duct.
Gallbladder hydrops is a rare condition resulting from chronic common duct obstruction or mucosal inflammation, in which the gallbladder becomes grossly distended by an uninfected clear mucoid fluid. Although it usually requires cholecystectomy, when the condition is associated with a mucocutaneous lymph node syndrome (Kawasaki disease), it tends to be self-limited and resolve spontaneously.
Causes:
Gallstones: In about 80% of patients, gallstones are clinically silent. Approximately 20% of patients develop symptoms over 15-20 years, that is, about 1% per year, and almost all become symptomatic before complications develop. Biliary-type pain, the typical clinical presentation, is due to obstruction of the bile duct lumen. The predictive value of other complaints (eg, intolerance to fatty food, indigestion) is too low to be clinically helpful. The incidence of gallbladder cancer developing in the setting of cholelithiasis is low, about 0.1% per year. Two main types of gallstones exist.
Cholesterol stones (85%): These are divided into 2 subtypes—pure (90-100% cholesterol) or mixed (50-90% cholesterol).
Pure stones often are solitary, whitish, and larger than 2.5 cm in diameter. Mixed stones usually are smaller, multiple in number, and occur in various shapes and colors. They tend to be arranged in laminated layers of an alternating thicker whitish cholesterol and a thinner dark pigment in a concentric pattern around a pigmented center (similar to the rings visible on the cross section of a tree). These stones tend to occur in residents of Western countries, and they usually are found in the gallbladder.
The risk factors associated with the development of cholesterol gallstones include obesity, a high-calorie diet, clofibrate therapy, gastrointestinal disorders involving major malabsorption of bile acids, cystic fibrosis with pancreatic insufficiency, and female sex and the use of oral contraceptives and other estrogenic medications. Coffee, ascorbic acid, has been shown to reduce the risk of symptomatic cholesterol gallstones.
Pigment stones (15%) occur in 2 subtypes—brown and black.
Brown stones are made up of calcium bilirubinate and calcium-soaps. Bacteria are involved in their formation via secretion of beta glucuronidase and phospholipase. The bacterial glycocalyx aggregates with the bile pigment and precipitates out of solution. These stones are more common in Asia and tend to form within the bile ducts. They frequently are associated with periampullary duodenal diverticula.
Black stones typically form in the gallbladder and result when excess bilirubin enters the bile and polymerizes into calcium bilirubinate. These stones are more common in patients with chronic hemolysis, alcoholic cirrhosis, and advanced age.
Acute calculus cholecystitis is an inflammation of the gallbladder that develops in the setting of an obstructed cystic or bile duct. It usually develops after 5 hours of biliary-type pain. The initial inflammation is caused by chemical irritation, and bacterial infection probably is a secondary event. A change in the perception of pain, classically a migration to the right upper quadrant, suggests transmural inflammation of the gallbladder, with involvement of the parietal peritoneum. Nausea and vomiting are common associated symptoms, and most patients are afebrile early in the course of the disease.
Mirizzi syndrome refers to common hepatic duct obstruction caused by an extrinsic compression from an impacted stone in the cystic duct. It has been estimated to occur in 0.7-1.4% of all cholecystectomies. It is often not recognized preoperatively, which can lead to significant morbidity and biliary injury, particularly with laparoscopic surgery.
Acute acalculous cholecystitis is the presence of an inflamed gallbladder in the absence of an obstructed cystic or common bile duct. It typically occurs in the setting of a critically ill patient (eg, severe burns, multiple traumas, lengthy postoperative care, prolonged intensive care) and accounts for 5% of cholecystectomies. Because abdominal pain, fever, and leukocytosis are relatively common in these patients and the signs and symptoms are not specific for acalculous cholecystitis, the physician must have a high index of suspicion to make the diagnosis. The etiology is thought to have an ischemic basis, and a gangrenous gallbladder may result. This condition has an increased rate of complications and mortality. An uncommon subtype known as acute emphysematous cholecystitis generally is caused by infection with clostridial organisms and occlusion of the cystic artery associated with atherosclerotic vascular disease and, often, diabetes.
Chronic cholecystitis is a common disorder that frequently is associated with gallstones. The clinical features are nonspecific, and cholescintigraphy initially may suggest the diagnosis. The pathogenesis is poorly understood but may be due to abnormal bile composition leading to chemical injury of the gallbladder mucosa. Histologic evidence of a mononuclear infiltrate, fibrosis, and epithelial metaplasia confirm the diagnosis. A subset of patients develops dystrophic calcifications within the fibrosis, leading to a porcelain gallbladder, which is a risk factor for gallbladder carcinoma.
Cholangitis is an infection of the biliary system, complicating benign and malignant obstruction of the biliary tract. The clinical presentation is quite variable depending on the nature of the illness, patient age, and condition of the patient. Charcot triad (ie, fever, right upper quadrant pain, jaundice) occurs in only 20-70% of cases. Hypotension and mental status changes also may accompany severe infection, a pentad described by Reynolds (1959). The organisms typically identified are enteric in origin, notably Escherichia coli, Streptococcus faecalis, Clostridium species, Klebsiella species, Enterobacter species, Pseudomonas species, and Proteus species. They probably enter the biliary system via portal bacteremia. No correlation exists between the severity of clinical manifestations and the presence or absence of pus in the biliary system; however, suppurative cholangitis is associated with a higher mortality rate.
Recurrent pyogenic cholangitis, also known as "oriental cholangiohepatitis," is prevalent in several parts of Asia and the Pacific Rim countries. It is limited to Asian immigrants in America, occurs in the second to fourth decades of life, and is associated with a lower socioeconomic class. It is initiated by parasitic infestation of the biliary ducts by Opisthorchis sinensis (formerly Clonorchis sinensis), in which the adult fluke may impair bile flow. In the setting of bile stasis and secondary bacterial infection, pigment stones form around ova and sets the stage for the intermittent obstruction leading to recurrent pyogenic cholangitis. Pathologic changes principally affect the intrahepatic bile ducts (curiously, more often the left duct).
PSC is a chronic cholestatic biliary disease characterized by nonsuppurative inflammation and fibrosis of the biliary ductal system. The cause is unknown but is associated with autoimmune inflammatory diseases, such as chronic ulcerative colitis and Crohn colitis (less commonly), and rare conditions, such as Reidel thyroiditis and retroperitoneal fibrosis. Most patients present with fatigue and pruritus and, occasionally, jaundice. The natural history is variable but involves progressive destruction of the bile ducts, leading to cirrhosis and liver failure. The clinical features of cholangitis (ie, fever, right upper quadrant pain, jaundice) are uncommon unless the biliary system has been instrumented.
Primary biliary cirrhosis
PBC is a progressive cholestatic biliary disease that presents with fatigue and itching or asymptomatic elevation of the alkaline phosphatase. Jaundice develops with progressive destruction of bile ductules that eventually leads to liver cirrhosis and hepatic failure. This autoimmune illness has a familial predisposition, in which even unaffected family members may have immunologic abnormalities, especially an increased serum immunoglobulin M (IgM) and an association with human leucocyte antigen (HLA)-DR8.
While numerous autoantibodies have been identified, antimitochondrial antibodies (AMA) are present in 95% of patients. AMA is a family of antibodies; those directed against the inner mitochondrial membrane antigen M2 in the 2-oxo-acid dehydrogenase complex are most specific for PBC. Circulating immune complexes also have been identified but are unlikely to play a pathogenic role. Circulating T lymphocyte levels initially are within the reference range and decline as the disease progresses. The histologic appearance of the bile duct destruction resembles hepatic allograft rejection and graft-versus-host disease of the liver and appears to be mediated by cytotoxic T lymphocytes.
Autoimmune cholangitis represents a rare, distinct disease entity. While it shares some features with PBC, the results of tests for AMA are negative, the levels of gamma globulin and IgM are lower, and the results of tests for fluorescent antinuclear antibody (FANA) and anti–smooth muscle antibody (ASMA) are positive more commonly.
Neoplasms of the biliary tract: Carcinoma of the biliary system manifests with clinical symptoms of weight loss (77%), nausea (60%), anorexia (56%), abdominal pain (56%), fatigue (63%), pruritus (51%), fever (21%), malaise (19%), diarrhea (19%), constipation (16%), and abdominal fullness (16%). Symptomatic patients usually have advanced disease, with spread to hilar lymph nodes before obstructive jaundice occurs. It is associated with a poor prognosis.
Gallbladder cancer: This uncommon malignancy affects 2.5 individuals per 100,000 population. It represents 54% of biliary tract cancers, and more than 6500 patients die from this disease in the United States each year. Cancer that develops in the infundibulum can produce hydrops of the gallbladder that is clinically indistinguishable from an obstructing stone.
Cholangiocarcinoma is an adenocarcinoma of the bile ducts. It may occur without associated risk factors, but it is associated more commonly with chronic cholestatic liver disease such as PSC, choledochal cysts, oriental cholangiohepatitis, and work-related handling of asbestos. Cholangiocarcinoma accounts for 25% of biliary tract cancers. Patients usually present with jaundice, a vague upper or right upper quadrant abdominal pain associated with anorexia, weight loss, and pruritus.
Ampullary cancer accounts for 8% of biliary tract cancers. It most commonly presents with painless jaundice or acute pancreatitis.
Biliary tract cysts: Cystic dilatation of the biliary tree is an uncommon abnormality. About half of the patients present with some combination of jaundice, abdominal pain, and an abdominal mass. The presence of these cysts often is associated with anomalous union of the pancreatic and biliary ductal system. This suggests that pancreatic juice enters the bile, causes a proteolytic and inflammatory injury to the duct wall, and leads to biliary cyst formation. The most commonly used classification scheme was proposed by Todani, which defines 5 cyst types, with groups I and IV having subtypes.
Type I involves a cystic dilatation of the extrahepatic biliary system. In subtype 1a (most common), the entire extrahepatic duct is diffusely involved. In subtype 1b (rare), a localized portion of the common bile duct is segmentally cystic. In subtype 1c (uncommon), the common bile duct is diffusely dilated.
Type II (rare) is a diverticulum of the extrahepatic bile duct.
Type III (uncommon) is a cystic dilatation of the intraduodenal portion of the common bile duct (sometimes referred to as a choledochocele).
Type IV has multiple cysts. Subtype IVa (uncommon) involves both the intrahepatic and extrahepatic biliary system, while subtype IVb (rare) has multiple cysts confined to the extrahepatic system.
Type V (rare) is characterized by single or multiple cysts involving the intrahepatic bile ducts (usually referred to as Caroli disease). Clinical symptoms usually are the result of associated complications such as cholangitis, choledocholithiasis, pancreatitis, hepatic abscess, cirrhosis, and biliary malignancy.