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Home , Abdominal pain, Jaundice

INTERNAL MEDICINE BOARD REVIEW DAVID L. LONGWORTH, MD, EDITOR JAMES K. STOLLER, MD, EDITOR

KSRTI SHETTY, MD Dr. Shetty is a resident in internal medicine at the Cleveland Clinic.

WILLIAM D. CAREY, MD Dr. Carey is head of the Section of and director of the transplantation pro- gram at the Cleveland Clinic. He was recently president of the American College of . , abdominal , and in a 43-year-old woman

WHAT IS THE DIAGNOSIS? 4 3-year-old Caucasian woman comes to the emergency room because of right On the basis of the clinical picture and upper that has lasted 2 1 laboratory data, what is the most likely days. The pain is dull and aching, is diagnosis? unrelated to food, and does not radiate. • Acute viral AShe notes that her tone has become more • Acute yellowish lately, and her is dark. • The patient says she has drunk three to • Acetaminophen toxicity four beers every day since the age of 18, and • Acute hepatic venous occlusion occasional drinks of vodka or gin on weekends. She abused intravenous drugs in her 20s, but This woman has the classic clinical triad of quit after successful drug rehabilitation. She alcoholic hepatitis: fever, jaundice, and tender has no history erf jaundice, , mele- .1 However, it is imperative to na, , or encephalopathy. She has lost exclude other causes of abdominal pain, such approximately 15 lb over the past 6 months, as obstruction, impaired hepatic and her appetite is poor. She takes no medica- venous outflow, and intra-abdominal or sys- tions, except for two to four acetaminophen temic infection. tablets daily. Nothing else in her medical his- Alcoholic hepatitis is caused by excessive tory is remarkable. ethanol consumption, but it develops in only On , the patient a minority of persons who drink heavily. appears cachexic, and her sclerae are deeply Autopsy studies reveal in fewer icteric. Her temperature is 39°C. Both parotid than 20% of alcoholics. The amount of glands are enlarged, but she has no palmar ery- ethanol necessary to produce clinically signif- thema or spider nevi. The liver is enlarged and icant disease varies markedly, but most tender to palpation. The is not palpa- patients with alcoholic hepatitis have con- ble, the bowel sounds are normal, and there is sumed more than 80 g/day for at least 15 no ascites. Cardiac auscultation discloses a years—a daily intake of 1 cup of 80-proof loud first heart sound, with a systolic ejection whiskey, 1 liter of 12% wine, or eight 12- murmur (grade 1/6) along the left sternal bor- ounce 6% beers.1 Women who drink are more der. The lung examination is normal. The prone to than are men, patient is drowsy with asterixis, but displays perhaps because they have lower gastric alco- no focal neurologic deficits. hol dehydrogenase activity, leading to less gas- TABLE 1 summarizes the patient's relevant tric detoxication and a greater fraction of laboratory values. alcohol reaching the liver.2

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 64 • NUMBER 4 APRIL 19972 1 3 Downloaded from www.ccjm.org on September 30, 2021. For personal use only. All other uses require permission. in alcoholic hepatitis ties of the TABLE 2 Alcoholic hepatitis differs from and biliary tract with a THE PATIENT'S LABORATORY in its biochemical profile. sensitivity approach- VALUES Aminotransferase levels. Typically, in ing 95%. Liver alcoholic hepatitis, the serum level of AST enlargement and het- Study Value (aspartate aminotransferase) is less than five erogeneity of texture times the upper limit of normal (ie, less than suggest intrinsic liver 10.9 g/dL 200 IU/L in 95% of cases, and rarely more disease. Cultures of Hematocrit 30.1 % than 300 IU/L). The ALT (alanine amino- the blood and of any Mean corpuscular volume 102 fL transferase) level is typically less than half the ascitic fluid would White blood cell count 14.9 X 109/L AST level. In contrast, acute viral hepatitis supplement the diag- Platelet count 97 X 109/L and drug-induced hepatic produce nostic workup, as Sodium 133 mEq/L extremely high levels of aminotransferases (up would serologic tests Potassium 3.6 mEq/L to 10 times normal). for hepatitis. Glucose 72 mg/dL An AST/ALT ratio greater than 2 has Blood urea nitrogen 11 mg/dL been suggested as a diagnostic test for alco- PREDICTING Creatinine 0.8 mg/dL holic hepatitis. However, in a Veterans THE OUTCOME Aspartate aminotransferase 214 U/L 5 Administration study, only 58% of patients Alanine aminotransferase 62 U/L with alcoholic hepatitis had a ratio that What are the 225 U/L exceeded 2. 2 most important Gamma-glutamyltransferase 674 U/L In contrast, the ALT level in viral hepati- determinants of 2.8 g/dL tis is usually higher than the AST level. prognosis in this (total) 12.0 mg/dL Gamma-glutamyltransferase (GGT) lev- patient? els are almost invariably elevated in alcoholic • Age Patient 17.0 seconds hepatitis. However, increases may reflect • Serum amino- Control 12.0 seconds microsomal enzyme induction rather than transferase levels • SEHBBa , and as a result, this enzyme is less Serum bilirubin useful for diagnosis and management. • level and prothrombin time Serum bilirubin and alkaline phos- Signs of portal hypertension phatase levels are usually elevated in alco- holic hepatitis, with values that tend to paral- A combination of clinical and laboratory fea- lel one another. Biliary tract obstruction, usu- tures predict the short-term prognosis of ally extrahepatic, is easily confused with alco- patients with alcoholic hepatitis. holic hepatitis, given that both produce dis- proportionate increases in alkaline phos- Indices of mortality phatase and exquisite hepatic tenderness. Two indices can be used to estimate the risk of Further tests, such as ultrasonography, are dying: the composite clinical and laboratory required to tell the difference (see below). index devised by Orrego et al4 (TABLE 2) and the The prothrombin time and albumin con- discriminant function proposed by Maddrey et centration are both used as measures of hepat- al.5 The former is used less in clinical practice, ic synthetic function; although these are often because it uses so many variables. abnormal in alcoholic hepatitis, they provide The discriminant function is much sim- little assistance in the initial diagnosis. pler to calculate: Acute hepatic venous occlusion (Budd- Chiari syndrome) is characterized by sudden 4.6 X[prothrombin time - control (in seconds)] + onset of abdominal pain and tender serum bilirubin (in mg/dL) hepatomegaly. It is almost invariably accom- panied by ascites (95% of cases), and the liver More than 50% of patients with a discrimi- function tests are usually surprisingly normal nant function greater than 32 die while in the or only mildly deranged. hospital. This formula has been validated prospectively as a predictor of survival and, The role of ultrasonography because it is readily applicable to clinical situ- The diagnostic test that would yield the most ations, is the indicator most often used in information at the least cost and degree of practice. invasiveness would be ultrasound scanning of Recent evidence6 suggests that serum the right upper quadrant. In experienced cytokine levels correlate with mortality in hands, ultrasonography can detect abnormali- acute alcoholic hepatitis, and may be useful in

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 64 • NUMBER 4 APRIL 19972 07 Downloaded from www.ccjm.org on September 30, 2021. For personal use only. All other uses require permission. HEPATITIS • SHETTY AND CAREY

refining the prognos- the short term, and should be hospitalized to COMPOSITE CLINICAL AND tic accuracy of the optimize her chances of survival. LABORATORY INDEX SCORE discriminant func- FOR ALCOHOLIC HEPATITIS tion. Other risk fac- Sobriety is essential tors for mortality Patients with alcoholic hepatitis must stop Sign or laboratory value Grade Score* include advanced drinking, but few can achieve total absti- age, encephalopathy, nence—fewer than 20% on questioning,3 and Encephalopathy 1-3 and low serum albu- fewer than 10% on objective testing.8 Referral Collateral circulation 1-2 min levels. None, to chemical dependence programs and various 3 however, is as accu- community-based resources is therefore para- 1 rate as Maddrey's mount. 2-3 discriminant func- However, abstinence does not guarantee Ascites 1-3 tion. improvement. In a study from Emory Spider nevi > 10 9 Weakness The AST and University, no patient recovered who con- Anorexia ALT levels do not tinued to drink, and of these, the hepatitis Prothrombin time correlate significant- progressed to within 18 months in 1 (seconds over control) 4-5 ly with survival. 38%. Nevertheless, only 27% of abstainers > 5 The clinical features returned to normal by the seventh month, Hematocrit (% of normal) 75-89.9 of portal hyperten- and hepatitis progressed to cirrhosis in as < 75 sion are not useful as many as 18%. Albumin level (g/dL) 2.5-2.9 prognostic indica- <2.5 tors.1 Diet therapy is difficult but important Bilirubin level (mg/dL) 2.1-8 Few studies have Malnutrition, often a prominent feature of addressed prognostic alcoholic hepatitis, increases the risk of Alkaline phosphatase level indicators in the dying.3 Experi-mental evidence suggests that (lU/dL) >330 long term. One of correction of malnutrition is essential for these used regression improvement of the liver disease. *A total score > 10 Indicates a risk of dying > 60% analysis to identify Unfortunately, the anorexia associated From Orrego et al, reference 4 three variables that with hepatitis often limits the replenishment predict a high risk of of nutrients. In a Veterans Administration BUMrMr.. . g progression from study in which hospitalized patients received a alcoholic hepatitis to well-balanced, 2500-kcal diet, only 63% of cirrhosis: continued alcohol use, female gen- the moderately ill patients and 53% of the der, and severity of initial injury (by severely ill patients met their estimated ener- histopathology).7 gy requirements. Multiple trials have failed to demonstrate TREATING ALCOHOLIC HEPATITIS that hyperalimentation alone improves sur- vival.3 Supplemental nutrition should be pro- What is the mainstay of therapy in this vided via enteral or parenteral routes only in 3 patient? patients who cannot tolerate oral feeding. • Abstinence from ethanol Expensive branched-chain amino acid mix- • Interferon alfa tures have not been shown to confer any • added benefit over standard total parenteral • Corticosteroids Abstinence from ethanol nutrition solutions, and are not routinely rec- ommended. and corticosteroids Vitamin and mineral deficiencies are The treatment of alcoholic hepatitis is largely common and require empiric replacement supportive. Although most patients do not therapy. A high-potency multivitamin prepa- require hospitalization, the patient described ration should be given that contains thi- above has more than a 50% risk of dying in amine, folate, pyridoxine, zinc, magnesium,

218 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 64 • NUMBER 4 APRIL 1997

Downloaded from www.ccjm.org on September 30, 2021. For personal use only. All other uses require permission. calcium, and vitamins B12, A, and D. Unless therapy from patients who have acquired loss is present, iron supplements should immunodeficiency syndrome (AIDS). be given only with caution, in view of the increased iron absorption seen in cirrhosis and Supportive therapy the high prevalence of hemosiderosis in alco- Treatment should be directed at improving holic liver disease. the chances of survival in the short term. Alcohol withdrawal symptoms, gastrointesti- Corticosteroids nal , or occult should be treated More than 20 years after corticosteroids were promptly, as these often cause morbidity and first studied for treating alcoholic hepatitis, death. their use remains controversial. However, two How long patients must stay in the hospi- randomized, placebo-controlled trials10'11 tal depends on the clinical response and the showed encouraging results: a 4-week course presence of intercurrent illness. Many patients of 32 mg of methylprednisolone (or an equiv- can be transferred directly to an inpatient alent) daily in patients with clinically severe alcoholic rehabilitation unit. Steroid therapy alcoholic hepatitis (discriminant function may be tapered rapidly over the fourth week of greater than 32) halved the mortality rate. therapy, as there is no evidence to suggest that Of note, the patients in these trials were longer treatment is beneficial. carefully selected: none had serious infections, Experimental treatments aim at stimulat- uncontrolled gastrointestinal bleeding, clini- ing hepatic regeneration with anabolic steroids cally significant mellitus, pancreati- and insulin glucagon infusions, decreasing tis, , or oxidative stress with propylthiouracil and infection. The efficacy of corticosteroids in cyanidanol, and preventing fibrosis with D- the presence of these comorbid conditions has penicillamine and .12 None of these not been established. has reproducibly decreased the mortality rate, There is a paucity of published data on and none can be recommended for general managing alcoholic hepatitis in patients with clinical use as yet. However, several ongoing coexistent infections with virus or clinical trials are exploring these and other human immunodeficiency virus (HIV). For therapies, which may in time expand the ther- now, it seems reasonable to withhold steroid apeutic options for alcoholic hepatitis, H

• REFERENCES 7. Pares A, Caballería J, Bruguera M, et al. Histological course of alcoholic hepatitis: influence of abstinence, sex and extent of hepatic damage. J 1. Mendenhall CL. Alcoholic hepatitis. In: Schiff L, Schiff ER, eds. Hepatol 1986; 2:33-37. Diseases of the liver. 7th ed. Philadelphia: JB Lippincott, 8. Orrego H, Blake JE, Blendis LM, Compton KV. Long-term treatment of 1993:856-87^. alcoholic liver disease with propyl-thiouracil. N Engl J Med 1987; 2. Frezza M, di Padova C, Pozzato G, Terpin M, Baraona E, Lieber CS. 23:1421-1427. High blood alcohol levels in women: role of decreased gastric alcohol 9. Galambos JT. Natural history of alcoholic hepatitis. III. Histological dehydrogenase activity and first pass metabolism. N Engl J Med 1990; changes. Gastroenterology 1972; 63:1026-1035. 322:95-99. 10. Ramond MJ, Poynard T, Rueff B, et al. A randomized trial of pred- 3. Mendenhall CL, Anderson S, Weesner RE, Goldberg S], Crolic KA. nisolone in patients with severe alcoholic hepatitis. N Engl J Med Protein-calorie malnutrition associated with alcoholic hepatitis: 1992;326:507-512. Veterans Administration Cooperative Study Group on Alcoholic 11. Carithers RL Jr, Herlong HF, Diehl AM, et al. Methylprednisolone Hepatitis. Air J Med 1984; 76(2):211-222. therapy in patients with severe alcoholic hepatitis: a randomized multi- 4- Orrego H, Israel Y, Blake JE, Medline A. Assessment of prognostic fac- center trial. Ann Intern Med 1989; 110:685-690. tors in alcoholic liver disease: toward a global quantitative expression of 12. Achord JL. Review of alcoholic hepatitis, and its treatment. Am J severity. Hepatology 1983; 3:896-905. Gastroenterol 1993; 88:1822-1831. 5. Maddrey WC. Boitnott JK, Bedine MS, Weber FL Jr, Mezey E, White R1 Jr. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology 1978; 75:193-199. ADDRESS REPRINT REQUESTS to William D. Carey, MD, Department of 6. McClain C, Hill D, Schmidt J, Diehl AM. Cytokines and alcoholic Gastroenterology, S40, The Cleveland Clinic Foundation, 9500 Euclid Avenue, liver disease. Semin Liver Dis 1993; 13:170-175. Cleveland, OH 44195

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