Metastatic Small Cell Carcinoma of the Lung: An Unusual Cause of Acute Fulminant Hepatic Failure
At autopsy, the left upper lobe of the patient’s lung was found to have a tan-white, firm, irregularly shaped 4.8-cm mass. The liver weighed 2,980 g (reference range: 1,400-1,600 g) and was diffusely infiltrated by tan-white masses comprising about 70% of the liver (Figure 1).
Histologic examination of the lung (Figure 2) and liver (Figure 3) masses revealed small, round, blue cells with high nucleocytoplasmic ratios, nuclear molding, and crushing artifact. The tumor cells were found to be positive for chromogranin and synaptophysin. The liver showed diffuse hepatocyte necrosis with few viable hepatocytes present. The autopsy case was signed out as SCLC with diffuse liver metastasis. 
Discussion
Acute FHF is a rare condition that often presents with sudden onset in which patients become encephalopathic due to hyperammonemia and exhibit marked elevations in the 2 aminotransferases, AST and ALT. A prior study of this condition reported on 6 patients, 5 of whom succumbed to the condition and 3 of whom were autopsied.4 The study found that both AST and ALT became rapidly elevated markedly such that the AST to ALT ratio was significantly greater than 1 and often exceeding 2, a pattern suggesting mitochondrial damage in hepatocytes resulting in release of intramitochondrial AST in addition to extramitochondrial AST.4
In addition, total protein and albumin were significantly decreased, and serum ammonia levels were markedly increased. All patients were encepaholopathic and were found to have disseminated intravascular coagulopathy. Five of the 6 patients had renal failure, including 2 with acute tubular necrosis, and electrolyte abnormalities, including hypernatremia, in one case due to circulating elevated levels of aldosterone. Two of the 6 patients were found to be consistently hypoglycemic, possibly caused by impaired glycogenolysis. Three of these patients were found to have had lactic acidosis. In this study, liver biopsy was unrevealing and showed only minimal changes even during the earlier noted changes in laboratory values. Total hepatocyte necrosis was found only at postmortem examination.
Causes of FHF
Previous studies have identified possible causes of FHF that include alcohol abuse and IV drug abuse giving rise to pan-hepatic hepatitis—both conditions giving rise to cirrhosis; multiple abdominal surgeries; drug (acetaminophen) overdose; fatty liver of pregnancy resulting in microvesicular steatosis of hepatocytes; hypotension (shock liver); and Reye syndrome, mainly in children but also reported in adults, in which there is a viral prodrome with fever followed by treatment with aspirin that progresses to acute FHF.
Metastatic cancer is not generally listed as a potential cause of FHF. Although cancer is a less common cause of this condition, metastasis-induced FHF that has been documented in the literature includes tumors of the breast, gastrointestinal tract, lung, nasopharynx, melanoma, and hematolymphoid malignancies, including leukemia, Hodgkin disease, non-Hodgkin lymphomas, and malignant histiocytosis.5-12
Small Cell Carcinoma as a Cause of FHF
Small cell carcinoma of the lung is a highly malignant neoplasm that often presents at an advanced stage. Most often, metastatic disease to the liver may result in some mild increase in ALT and obstructive symptoms. However, diffuse sinusoidal infiltration of the tumor is most likely to present with hyperacute liver failure.13 A literature review of all small cell carcinomas in the liver presenting with acute FHF shows a consistent morphologic pattern of diffuse parenchymal infiltration,some that initially present with acute hepatic failure with no known history of liver disease.13-25 Imaging studies sometimes are difficult to interpret and may fail to detect infiltration of the tumor because of diffuse involvement of the liver parenchyma. Malignant infiltration of the liver should be one of the considerations in cases of unexplained hepatomegaly.
As found in the authors’ prior study, coagulopathy, renal failure (final creatinine was 3.2 mg/dL) as well as hypoglycemia are oftentimes seen, all of which were found in the patient in this study.4 (Coagulopathy was indicated by the low platelet count and elevated PT and aPTT.) Laboratory findings for FHF include rapid increases in serum ALTs such that the AST:ALT ratio is significantly greater than 1 and in which total protein and albumin are significantly decreased. Often there is hyperammonemia as was present in the current case.
A study has been performed to develop serodiagnostic markers to distinguish malignant from nonmalignant causes of FHF on 4 patients with tumor-induced FHF and 12 patients with FHF due to other causes. It was found that that there was an increase in the lactate dehydrogenase (LDH) to ALT ratio as well as elevated uric acid levels in the 4 patients with FHF not found in any of the 12 patients with nonmalignant causes of this condition.19 Although LDH was not measured in this case, in view of the patient’s history of gout, the LDH/uric acid ratio may not have been discriminating.
Conclusion
Although rare, metastatic small cell carcinoma should be included in the clinical differential diagnosis of patients presenting with acute FHF with no other obvious medical etiology. Accurate and timely diagnosis is important to better guide management of these patients.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
