Gerald Klatskin

The Prognostic Importance of Clinical and Histologic Features in Asymptomatic and Symptomatic Primary Biliary Cirrhosis

To determine the life expectancy of patients with primary biliary cirrhosis, we analyzed survival data from 280 patients with either symptomatic (243) or asymptomatic (37) disease. Patients were followed for up to 19 years (mean, 6.9 years). The average length of survival was 11.9 years--nearly twice that reported in other studies. In contrast, over a 12-year period the survival of the asymptomatic patients after diagnosis did not differ from that of a control population matched for age and sex. Jaundice, weight loss, hepatomegaly, splenomegaly, and ascites were each associated with a poor prognosis. Prognosis also correlated with the histologic stages of hepatic fibrosis, cholestasis, and periportal-cell necrosis. A multivariate analysis of clinical features revealed that at the onset of disease, age, hepatomegaly, and elevated levels of serum bilirubin were independent discriminators of a poor prognosis. A histologic finding of fibrosis limited to portal areas improved this discrimination, correlating with prolonged survival. No other factors enchanced the prediction of risk.

Pattern of necrosis in acute viral hepatitis. Prognostic value of bridging (subacute hepatic necrosis).

Abstract Of 170 patients with biopsy-documented acute viral hepatitis, 52 exhibited zones of hepatic necrosis and collapse that bridged adjacent portal triads or central veins (or both), a lesion classified as subacute hepatic necrosis (SHN). Whereas the clinical course in the 118 patients with the classic type of spotty necrosis (CH) was relatively benign, 19 per cent of those with SHN lesions died, and cirrhosis developed in 37 per cent. Ascites, edema and hepatic coma, which occurred in approximately a quarter of the SHN patients, were the only clinical manifestations that clearly distinguished between the two groups. The pattern of hepatic necrosis characterized by intralobular and interlobular bridging of portal triads or central veins, when found during the acute phase of viral hepatitis, indicates a severe form of the disease that may lead to fatal hepatic failure or the development of cirrhosis in a significant number of patients.

Hepatic disease in erythropoietic protoporphyria

Two sisters had erythropoietic protoporphyria and a spectrum of liver disease. One (F.B.) died in hepatic failure within 3 months after the development of jaundice. Only 10 months before she died, she had exhibited only bromsulfalein retention and a borderline increase in serum transaminase. Surgical exploration because of the jaundice revealed patency of the bile ducts which was confirmed at autopsy. Wedge biopsy and autopsy specimens of liver showed an active cirrhosis with massive amounts of protoporphyrin in Kupffer cells, portal histiocytes, bile canaliculi and parenchymal cytoplasm. The other sister (L.R.) had never had symptomatic liver disease and only a slight increase in serum transaminase and bromsulfalein retention. On needle biopsy, the liver specimen showed portal inflammation with erosion of limiting plates, occasional bridging between triads and central areas of cell dropout. Protoporphyrin pigment was present in portal histiocytes, areas of central collapse and, more rarely, in parenchymal cytoplasm. These studies demonstrate that significant, progressive hepatic disease may occur insidiously in erythropoietic protoporphyria, and that once jaundice appears it may be followed rapidly by fatal hepatic failure.

Arteriohepatic Dysplasia: A Benign Syndrome of Intrahepatic Cholestasis with Multiple Organ Involvement

Arteriohepatic dysplasia (Alagilles syndrome) is presumed to be one of the familial intrahepatic cholestatic syndromes, all of which present with neonatal jaundice or failure to thrive, or both. We report the findings in five patients with this syndrome, four of whom have been followed into adulthood. In addition to hepatic dysfunction, patients had abnormalities of the cardiovascular system, eyes, bones, central nervous system, kidney, endocrine system, and habitus. Analysis of these cases allows a more complete characterization of this syndrome and shows that the cholestasis improves, although the abnormalities of the hands and face become more pronounced, with age. Patients with arteriohepatic dysplasia display the variability in expression seen in many autosomal-dominant conditions. New findings in the eye and spine provide markers specific for this syndrome and serve to differentiate it from other forms of cholestatic liver disease.

Glucose Homeostasis in Viral Hepatitis

Abstract Fasting hypoglycemia (plasma glucose level below 60 mg per 100 ml) was observed in eight of 15 consecutive patients with acute viral hepatitis. Plasma insulin levels were decreased 30 per cent in the eight hypoglycemic patients. The plasma glucose response to glucagon was 1/3 that of normal controls, and was not improved by a high-carbohydrate diet. In normal subjects, glucagon elicited a prompt reduction in plasma amino acid levels that was greatest for alanine and glycine. No consistent reduction in amino acid concentration after glucagon administration was observed in the hepatitis group. Liver glycogen content, determined histologically, was markedly reduced in the patients with hepatitis. Acute viral hepatitis results in serious impairment in hepatic glycogen synthesis and gluconeogenesis and frequently gives rise to fasting hypoglycemia.

The effect of sodium taurocholate on the hepatic metabolism of sulfobromophthalein sodium (BSP). The role of bile flow

The influence of bile salts on the hepatic metabolism of sulfobromophthalein sodium (BSP) was studied in the perfused rat liver. During sodium taurocholate infusions, hepatic uptake of BSP from plasma was increased and appeared to be related to an enhanced transit of BSP from liver into bile. BSP-glutathione conjugation was not affected by the bile salt infusions, although bile salts inhibited the enzyme system in vitro. The major effect of bile salts was to increase the BSP transport maximum (Tm). When sodium taurocholate was infused in saline at a rate of 30 mumoles/hr, both bile flow and the BSP Tm increased, and remained at peak levels of 1.5 +/-0.12 mul/min per g liver and 21 +/-3.0 mug/min per g liver, respectively. In contrast, during saline infusion alone both levels were significantly lower (1.06 +/-0.17 mul/min per g liver and 15.8 +/-4.16 mug/min per g liver, respectively), and both fell progressively after the 2nd hr of perfusion. This decline in bile flow and BSP Tm was associated with a decrease in biliary bile salt excretion and was reversed by adding bile salts to the perfusate. Since the biliary concentration of BSP remained within a narrow range in all experiments, the BSP Tm was primarily determined by the rate of bile flow. Dependence of BSP Tm on the rate of bile production was further confirmed by changing the temperature of the perfusate during a constant infusion of taurocholate. BSP Tm paralleled temperature-induced changes in bile flow irrespective of changes in the level of bile salt excretion. Since the biliary concentration of BSP remained within a narrow range in all experiments, the concentrating capacity for BSP in bile may be the major limiting factor in BSP transport. Thus two independent factors appear to determine the BSP Tm: the bile BSP concentration, and the rate of bile production. Because taurocholate enhanced BSP transport only when it increased bile production, its effect on the BSP Tm appears to be attributable to its choleretic properties.

Relationship of Serum α-Fetoprotein to the Severity and Duration of Illness in Patients With Viral Hepatitis

Using a radioimmunoassay which detect concentrations of alpha-fetoprotein as low as 5 ng per ml, 38% of 176 patients with viral hepatitis compared with health volunteers and patients with chronic diseases not affecting the liver. When separated into two groups based on histological classification of liver biopsy specimens, differences in the degree and frequency of increased serum alpha-fetoprotein were related to the severity of the hepatic lesion. Of 75 patients with the lesion of viral subacute hepatic necrosis, in which zones of necrosis bridge adjacent portal triads or central veins, 52% had increased values, and 12% had levels ranging from 500 to 3300 ng per ml. In contrast, only 28% of the 101 patients without bridging necrosis had increased values, and none had levels that exceeded 500 ng per ml. In the patients with subacute hepatic necrosis, comparison of alpha-fetoprotein concentrations with the duration of illness indicated that the protein rose to peak levels in serum as the SGOT was declining. This was confirmed by serial observations in 10 patients. Thus, the increase of alpha-fetoprotein in the sera of patients with severe hepatitis occurs as liver necrosis is subsiding. Due to other known features of alpha-fetoprotein, it is intriguing to speculate that the increase in serum levels of this protein in viral hepatitis reflects hepatic regeneration after parenchymal damage.

HEPATIC GRANULOMATA: PROBLEMS IN INTERPRETATION

Granulomata occur in the liver not only in patients with systemic granulomatous disease, but also in a variable number with underlying liver disease and in a heterogeneous group of disorders that appear to be neither hepatic nor granulomatous in nature. The hepatic granulomata found in association with liver disease are rarely attributable to complicating systemic granulomatous disease, and probably represent a nonspecific response to the underlying hepatic disease. In the heterogeneous group of diseases that appear to be neither hepatic nor granulomatous in nature, hepatic granulomata may (in some instances) represent a nonspecific response to such conditions as intraabdominal malignancy and ulcerative bowel disease. However, in others, particularly those with unexplained prolonged fever, hepatic granulomata may be attributable to specific agents that are overlooked or escape detection by currently available diagnostic measures. The etiology of hepatic granulomata can seldom be established on histological grounds alone, and usually requires collateral clinical and laboratory evidence for identification.

Heritable urea cycle enzyme deficiency-liver disease in 16 patients.

The liver mitochondrial enzymes ornithine transcarbamylase and carbamyl phosphate synthetase I catalyze the first two steps in the Krebs-Henseleit pathway from ammonia to of either of these enzymes has been associated with severe and sometimes fatal hyperammonemia in infancy and childhood, but liver histology has usually been described as normal. The Reye syndrome also causes severe hyperammonemia and produces characteristic light microscopic changes in the liver. In addition, OTC and CPS activities have been shown to be depressed and it has been suggested that some cases of the Reye syndrome may reflect an inborn defect in OTC which predisposes the patient to the Reye syndrome. Review of the histopathology of 15 liver specimens from 13 patients with OTC deficiency and three liver specimens from three patients with CPS deficiency has disclosed the following: (1) hemizygous male infants with X-linked OTC deficiency had essentially normal liver histology, although fatally affected with extreme hyperammonemia; (2) in contrast, almost all heterozygous female children and adults had some histologic abnormalities, including nine with minor degrees of steatosis and eight with focal cell necrosis and inflammation, two of whom had piecemeal necrosis and stellate portal scarring; (3) livers from heterozygotes had discrete clusters of larger, pale-staining hepatocytes; (4) female heterozygotes had abnormal liver function, even after the hyperammonemia was controlled; (5) CPS deficient patients had essentially normal liver histology; and (6) neither OTC nor CPS deficiency was associated with a histologic picture which resembled that seen in the Reye syndrome.

Serum α-Fetoprotein in Patients with Massive Hepatic Necrosis

Serum concentrations of a-fetoprotein (AFP) were measured by radioimmunoassay in 12 patients with massive hepatic necrosis, 11 of whom died. Levels were significantly elevated after the 8th day of illness in 8 of the 9 patients who died between the 10th and 60th day, and in the 1 patient who survived. All 9 patients with increased levels of serum AFP exhibited histological evidence of hepatic regeneration. These findings indicate that the rise in serum AFP in massive hepatic necrosis is related to the duration of survival after the onset of illness, but does not necessarily imply ultimate recovery. Because available evidence suggests that the serum AFP level reflects hepatic regenerative activity, it appears that the onset of regeneration in fulminant hepatitis is delayed until the 2nd week of illness.