High risk of primary liver cancer in a cohort of 179 patients with Acute Hepatic Porphyria

Background/aims

Previous studies have indicated a high risk of hepatocellular carcinoma in acute hepatic porphyrias. In this retrospective study we present the incidence of primary liver cancer and clinical characteristics in a cohort of 179 acute porphyria patients above the age of 50 years.

Methods

Twenty-three cases with primary liver cancer were found either by a surveillance program or due to clinical suspicion. Standardized rate ratio was used to estimate the relative risk of primary liver cancer after indirect standardization. Survival data were calculated using the Kaplan-Meier method.

Results

The mean age at diagnosis was 69 years. Hepatocellular carcinoma was found in 19 patients while four patients had cholangiocarcinoma or a combination of the two. Four patients had underlying cirrhosis. Mean tumour size was 4.3 cm in the surveillance group and 10.3 cm in the non-surveillance group (p?=?0.01). The overall relative risk of primary liver cancer was 86 above the age of 50: 150 for women and 37 for men. Mean survival time was 5.7 years.

Conclusion

Acute hepatic porphyria carries a high risk of primary liver cancer above the age of 50 which warrants ultrasound surveillance. Sex distribution and frequency of cirrhosis differs from more common aetiologies of primary liver cancer.     

Hepatic porphyrias

The porphyrias are metabolic disorders characterized by abnormal heme biosynthesis with excessive accumulation and excretion of porphyrias or porphyrin precursors. Defects in the enzymes of the heme biosynthetic pathway result in porphyria. Several of the disorders have been classified as hepatic because the major site of the biochemical defect has been localized to the liver. This article describes the enzymes of the heme biosynthetic pathway, the clinical features of the hepatic porphyrias and management of the disorders.     

Porphyrien – was ist gesichert?

Porphyrias are caused by enzyme defects of heme biosynthesis. According to their clinical presentation and to each affected pathway, they are categorized into acute and non-acute as well as hepatic and erythropoietic porphyrias. Acute hepatic porphyrias, e.g. acute intermittent porphyria (AIP), porphyria variegata (VP), hereditary coproporphyria (HCP) and 5?aminolevulinic acid dehydratase-deficient porphyria (ALADP) are characterized by accumulation of the porphyrin precursors 5?aminolevulinic acid (ALA) and porphobilinogen (PBG) that correlate with severe abdominal, psychiatric, neurological or cardiovascular symptoms. Additionally, skin photosensitivity can occur in VP and less frequently, in HCP. Decisive for the diagnosis of acute hepatic porphyrias are a >4-fold elevated urinary excretion of ALA in ALADP and ALA and PBG in all other acute porphyrias. First-line treatment of an acute porphyria attack includes intensive care with pain management, sufficient caloric supply, strict avoidance of porphyrinogenic drugs and elimination of other triggering factors. Heme therapy is indispensable in case of developing neurological symptoms and clinical worsening despite first-line measures. Non-acute porphyrias, mainly porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP) and X?linked protoporphyria (XLP) display accumulation of porphyrins in the skin and/or liver resulting in photosensitivity up to possible liver damage. Patients with PCT benefit from iron depletion, low-dose chloroquine treatment and/or hepatitis C virus elimination. Afamelanotide is associated with better sunlight tolerance in patients with EPP and XLP. Moreover, innovative therapies that highly selectively address dysregulated steps of the heme biosynthetic pathway are currently under clinical trial.     

Molecular aspects of the inherited porphyrias

The porphyrias are diseases due to marked deficiencies of enzymes of the haem biosynthetic pathway (Fig. 1). Except for the first enzyme of the pathway, delta-aminolevulinate synthase (ALAS), deficiencies in seven other enzymes are associated with the various forms of porphyria (Fig. 2). Porphyrias can be classified as either hepatic or erythroid, depending on the major site of production of porphyrins or their precursors. The pathogenesis of all inherited porphyrias has now been defined at the molecular level, and it is clear that there is a great deal of genetic heterogeneity in each porphyria [1].     

Porphyrias

Porphyrias are metabolic disorders of the heme biosynthesis. Clinically, they can be differentiated into acute and non-acute porphyrias. The symptomatic phase of acute hepatic porphyrias is characterized by overproduction of neurotoxic porphyrin precursors and porphyrins. Acute intermittent porphyria, Variegate porphyria, Hereditary coproporphyria and Doss porphyria belong to this group of metabolic disorders. The clinical presentation of the acute hepatic porphyria syndrome includes abdominal, psychiatric, neurological and cardiovascular symptoms. The diagnosis is based on a tenfold increased urinary excretion of porphobilinogen (apart from Doss porphyria). Besides symptomatic therapy with non-porphyrinogenic drugs, electrolyte compensation and intensive monitoring, intravenous administration of glucose and heme arginate is established for treatment. Among the non-acute types like Porphyria cutanea tarda, Erythropoietic protoporphyria and Congenital erythropoietic porphyria, the accumulated porphyrins cause photosensitivity of the skin up to severe liver damage. The location of the deficient enzyme within the heme biosynthesic pathway determines the pattern of the accumulated porphyrins. Besides light protection, there are different therapies depending on the type of non-acute porphyria. Ultimately, liver transplantation may be considered in therapy-resistant cases of acute hepatic porphyrias and bone marrow transplantation in severe cases of erythropoietic porphyrias.     

Porphyrien

Porphyrias are metabolic disorders of the heme biosynthesis. Clinically, they can be differentiated into acute and non-acute porphyrias. The symptomatic phase of acute hepatic porphyrias is characterized by overproduction of neurotoxic porphyrin precursors and porphyrins. Acute intermittent porphyria, Variegate porphyria, Hereditary coproporphyria and Doss porphyria belong to this group of metabolic disorders. The clinical presentation of the acute hepatic porphyria syndrome includes abdominal, psychiatric, neurological and cardiovascular symptoms. The diagnosis is based on a tenfold increased urinary excretion of porphobilinogen (apart from Doss porphyria). Besides symptomatic therapy with non-porphyrinogenic drugs, electrolyte compensation and intensive monitoring, intravenous administration of glucose and heme arginate is established for treatment. Among the non-acute types like Porphyria cutanea tarda, Erythropoietic protoporphyria and Congenital erythropoietic porphyria, the accumulated porphyrins cause photosensitivity of the skin up to severe liver damage. The location of the deficient enzyme within the heme biosynthesic pathway determines the pattern of the accumulated porphyrins. Besides light protection, there are different therapies depending on the type of non-acute porphyria. Ultimately, liver transplantation may be considered in therapy-resistant cases of acute hepatic porphyrias and bone marrow transplantation in severe cases of erythropoietic porphyrias.     

Porphyrias in Japan: Compilation of All Cases Reported through 2002

The first case of porphyria on record in Japan was a patient with congenital erythropoietic porphyria (CEP) reported by Sato and Takahashi in 1920. Since then until the end of December 2002, 827 cases of porphyrias have been diagnosed from characteristic clinical and/or laboratory findings (463 males, 358 females, and 6 of unknown sex). Essentially all inherited porphyrias have been found in Japan, with the incidences and clinical symptoms generally being similar to those reported for other countries. The male-female ratio was approximately 1:1 for CEP, whereas it was higher for erythropoietic protoporphyria. In contrast, preponderances of female patients exist with acute hepatic porphyrias, such as acute intermittent porphyria (AIP), variegate porphyria (VP), and hereditary coproporphyria (HCP), and with undefined acute porphyria. Although porphyria cutanea tarda (PCT) is believed to be increasing recently in women in other countries because of smoking and the use of contraceptives, it is still by far more prominent in males in Japan than in females. The recent increasing contribution of hepatitis C virus infection to PCT in Japan has also been recognized. but there have been no PCT cases in Japan with HFE gene mutations. Familial occurrence and consanguinity were high for CEP, as expected; however, significant consanguinity was also noted in families where CEP, AIP, HCP, VP, or PCT occurred as a single isolated case without a family history of disease. This survey also revealed that as many as 71% of acute hepatic porphyria cases were initially diagnosed as nonporphyria and later revised or corrected to porphyria, indicating the difficulty of diagnosing porphyria in the absence of specific laboratory testing for porphyrins and their precursors in urine, stool, plasma, and erythrocyte samples.     

Variegate porphyria in a 46‐year‐old patient taking sibutramine for weight loss

The acute hepatic porphyrias can cause life‐threatening attacks of neurovisceral symptoms that mimic other acute medical conditions. Variegate porphyria caused by mutations in the protoporphyrinogen oxidase (PPOX) gene is a latent disorder characterized by exacerbations induced by fasting, alcohol consumption or certain drugs. We describe the case of a 46‐year‐old female patient presenting with a first episode of symptomatic porphyria after 10 d of sibutramine treatment for weight loss. Genetic analysis showed a heterozygous R168H hot spot mutation in the PPOX gene. A putative effect of sibutramine on the hepatic haem biosynthetic pathway and reduced food intake have likely caused this exacerbation of a porphyria attack. Although this may be the first case report of this kind, the risk of acute porphyria should be considered in patients using pharmacotherapy for obesity.     

Hematologic aspects of the porphyrias

The porphyrias are disorders that can be inherited and acquired, in which the activities of the enzymes of the heme biosynthetic pathway are partially or almost totally deficient. There are 8 enzymes involved in the synthesis of heme, and, with the exception of the first enzyme, an enzymatic defect at every step leads to tissue accumulation and excessive excretion of porphyrins and/or their precursors, such as delta-aminolevulinic acid and porphobilinogen. Whereas heme, the final product of the biosynthetic pathway, is biologically important, porphyrins and their precursors are not only useless but also toxic. Porphyrias can be classified as either photosensitive or neurologic, depending on the type of symptoms, but some porphyrias cause both photosensitive and neurologic symptoms. Alternatively, they can be classified either hepatic or erythropoietic, depending on the principal site of expression of the specific enzymatic defect. The tissue-specific expression of porphyrias is largely due to the tissue-specific control of heme pathway gene expression, particularly at the level of delta-aminolevulinate synthase, the first and the rate-limiting enzyme of heme biosynthesis. In this chapter, hematologic aspects of the erythropoietic porphyrias will be described. The 3 major erythropoietic porphyrias are congenital erythropoietic porphyria (CEP), hepatoerythropoietic porphyria (HEP) and erythropoietic protoporphyria (EPP).     

Transcatheter arterial chemoembolization of hepatocellular carcinoma: a Japanese experience

Hepatocellular carcinoma is one of the most common causes of cancer death in Japan and in 80% of cases is associated with chronic liver disease caused by hepatitis C virus. Poor hepatic function reserve due to underlying cirrhosis is the primary factor which limits extended surgical resection in many cases. Furthermore, in patients treated by curative resection, high incidence of recurrent tumors or/and newly developed tumor in the residual liver was reported. Therefore, the aim of various therapeutic options such as operation, percutaneous ethanol injection, radiofrequency coagulation therapy and transcatheter arterial chemoembolization should be the local control of hepatocellular carcinoma. Transcatheter hepatic arterial chemoembolization has a main role for the multidisciplinary treatment for hepatocellular carcinoma with this biological behavior.     

Resected cases of hepatocellular carcinoma detected after interferon therapy for chronic hepatitis C

BACKGROUND/AIMS: Interferon therapy decreases the incidence of hepatocellular carcinoma in patients infected with hepatitis C virus. However, hepatocellular carcinoma was detected after interferon therapy in some patients. METHODOLOGY: Of the 167 patients who underwent liver resection for hepatitis C virus-related hepatocellular carcinoma between 1993 and September 1998, the carcinoma was detected after interferon therapy in 11 patients. The clinicopathologic findings in these 11 patients were studied. RESULTS: The response to interferon was complete (n = 4), partial (n = 4), or no response (n = 3). Hepatocellular carcinoma was detected 2 months to 3 years 9 months, after interferon therapy. The interval period from the end of interferon therapy to the detection of the carcinoma were significantly correlated with the longest diameter of the main tumor (P = 0.0043), indicating that most carcinomas have already developed before the end of interferon therapy. In one non-responder, multicentric carcinogenesis occurred after liver resection for primary hepatocellular carcinoma. Another patient with advanced hepatocellular carcinoma died of the recurrence. CONCLUSIONS: Surveillance for hepatocellular carcinoma must be performed even in patients successfully treated with interferon because occult carcinoma may have developed before or during the therapy.     

Prevalence of hepatic iron overload and association with hepatocellular cancer in end-stage liver disease: results from the National Hemochromatosis Transplant Registry.

BACKGROUND: It is unclear whether mild to moderate iron overload in liver diseases other than hereditary haemochromatosis (HH) contributes to hepatocellular carcinoma. This study examined the association between hepatic iron grade and hepatocellular carcinoma in patients with end-stage liver disease of diverse aetiologies. METHODS: The prevalence of hepatic iron overload and hepatocellular carcinoma was examined in 5224 patients undergoing liver transplantation. Explant pathology reports were reviewed for the underlying pathological diagnosis, presence of hepatocellular carcinoma and degree of iron staining. The distribution of categorical variables was studied using chi(2) tests. RESULTS: Both iron overload and hepatocellular carcinoma were the least common with biliary cirrhosis (1.8 and 2.8% respectively). Hepatocellular carcinoma was the most common in patients with hepatitis B (16.7%), followed by those with hepatitis C (15.1%) and HH (14.9%). In the overall cohort, any iron overload was significantly associated with hepatocellular carcinoma (P=0.001), even after adjustment for the underlying aetiology of liver disease. The association between hepatic iron content and hepatocellular carcinoma was the strongest in patients with biliary cirrhosis (P<0.001) and hepatitis C (P<0.001). CONCLUSIONS: Iron overload is associated with hepatocellular carcinoma in patients with end-stage liver disease, suggesting a possible carcinogenic or cocarcinogenic role for iron in chronic liver disease.     

Endothelial cell marker expression in dysplastic lesions of the liver: an immunohistochemical study

BACKGROUNDS/AIMS: Hepatocellular carcinoma usually contains continuous capillary vessels lacking the differentiation markers specific for normal sinusoidal endothelial cells. We therefore aimed to search for alterations in endothelial cell marker expression in precancerous liver lesions. METHODS: Expression of the endothelial cell markers CD31, CD34 and BNH9 was analyzed in 138 dysplastic lesions from 40 cirrhotic patients (20 with and 20 without hepatocellular carcinoma). RESULTS: No expression of the three endothelial cell markers was detected in cirrhotic nodules and in non dysplastic regenerative macronodules. The three markers were detected in 29.8% of dysplastic lesions and 47% of hepatocellular carcinomas. At least one marker was detected in 75% of dysplastic lesions and 100% of hepatocellular carcinomas. The three markers were more frequently expressed in areas of small cell than of large cell change (34 vs 10%). No correlation was found with the grade of dysplasia, the occurrence of arterialization and the association with hepatocellular carcinoma. CONCLUSIONS: Alterations in the hepatic microcirculation comparable to those observed in hepatocellular carcinoma are present in a significant proportion of dysplastic lesions of the liver and may be indirect markers of the process of liver carcinogenesis.     

Incidence of hepatocellular carcinoma in chronic hepatitis C after interferon therapy

BACKGROUND/AIMS: We investigated the rate of occurrence and the risk factors for hepatocellular carcinoma in chronic hepatitis C patients who received interferon therapy. METHODOLOGY: We followed 413 chronic hepatitis C patients for more than 6 years after interferon therapy and assessed the following patient characteristics: age, sex, platelet count, response to interferon, hepatitis C virus RNA level, hepatitis C virus genotype, liver histology, and changes in serum alanine aminotransferase levels. RESULTS: Hepatocellular carcinoma was found in 21 patients after interferon therapy. The factor most related to the occurrence of hepatocellular carcinoma was changes in serum alanine aminotransferase levels (univariate analysis, P < 0.0001; multivariate analysis, P = 0.0013), followed by age (univariate analysis, P = 0.0003; multivariate analysis, P = 0.0029). A significant difference was observed in the platelet count and response to interferon based on univariate analysis alone (P = 0.0096, P = 0.0241, respectively), however no significant differences were noted in the other factors. The course of serum alanine aminotransferase levels following interferon therapy rather than the eradication of hepatitis C virus was found to be the factor most profoundly involved in liver carcinogenesis. CONCLUSIONS: Even if interferon therapy fails to eradicate the hepatitis C virus, maintaining low serum alanine aminotransferase levels post-interferon therapy would reduce the risk of hepatocellular carcinoma in chronic hepatitis C.     

Patterns of and risk factors for recurrence after liver resection for well-differentiated hepatocellular carcinoma: a special reference to multicentric carcinogenesis after operation

BACKGROUND/AIMS: We studied the patterns of, and risk factors for, recurrence after resection of well-differentiated hepatocellular carcinoma to make a strategy for such carcinoma. METHODOLOGY: The subjects were 36 patients who underwent liver resection for well-differentiated hepatocellular carcinoma. Multicentric carcinogenesis after the operation (multicentric recurrence) was diagnosed when a recurrent tumor included a component of well-differentiated hepatocellular carcinoma. Tumor-free survival rates of patients with various risk factors were calculated and differences between groups were evaluated. For multivariate analysis, Cox's proportional hazard model was used. RESULTS: All recurrent tumors after operation were of multicentric origin. Univariate analysis showed a history of blood transfusion, high alpha-fetoprotein concentration (> 20 ng/ml), and low platelet count (< 10(5)/mm3) to be significant factors. By multivariate analysis, a history of blood transfusion and a low platelet count were independent risk factors. Nonanatomic resection was not a risk factor. CONCLUSIONS: In patients with well-differentiated hepatocellular carcinoma, especially with risk factor(s) for multicentric recurrence, not only anatomic but also nonanatomic resection (partial resection) are indicated for a primary tumor, because almost all recurrent tumors are of multicentric origin. After resection of well-differentiated hepatocellular carcinoma, careful monitoring for multicentric recurrence is important in patients with risk factors.     

Extra-hepatic hepatocellular carcinoma presenting as obstructive jaundice

Hepatocellular carcinoma is a neoplasm with a uniformly poor prognosis. Risk factors for its development include chronic hepatitis B or C infection, haemochromatosis and alpha-1-antitrypsin deficiency, but individuals with any type of chronic liver disease are predisposed. The incidence is significantly higher in Asia and Africa although it has been noted to be increasing in the United States. We present a patient with notable atypical clinical features for hepatocellular carcinoma. The patient had neither predisposing risk factors nor a primary liver lesion causing obstructive jaundice. After multiple tissue specimens were obtained, the final pathological diagnosis was established. Hepatocellular carcinoma generally requires a surgical cure, but patients who are icteric often portend poorer prognoses. For those at high risk, screening may be indicated to identify early curative treatment.     

Risk factors for massive blood loss during liver resection for hepatocellular carcinoma in patients with cirrhosis

BACKGROUND/AIMS: Liver resection for hepatocellular carcinoma in patients with cirrhosis carries risk of major hemorrhage and sometimes requires blood transfusion. We investigated risk factors for massive blood loss during liver resection and indications for storing blood for autologous intraoperative transfusion. METHODOLOGY: We analyzed clinical records of 100 patients with cirrhosis who underwent liver resection for hepatocellular carcinoma. Autologous blood was stored preoperatively for 19 patients. RESULTS: Intraoperative blood loss ranged from 5 to 3000 mL (mean, 640). Liver resection was performed without transfusion in 67 patients and with autologous blood storage in 17 patients not receiving homologous blood. In the other 16 patients, homologous blood was transfused. Univariate analysis identified youth, large tumors (> 4cm), major hepatectomy, portal tumor involvement, hepatic vein involvement, and prolonged operation time as risk factors for massive blood loss; multivariate analysis identified portal involvement and hepatic vein involvement as independent risk factors. Blood loss exceeded 1000 mL in the 4 transfused group B patients and 3 of the 4 patients had hepatic vein involvement. CONCLUSIONS: Portal involvement and hepatic vein involvement were risk factors for massive blood loss during liver resection for hepatocellular carcinoma in patients with cirrhosis. Autologous blood storage is indicated in patients with such risk factors.     

Association of nonalcoholic fatty liver disease and liver cancer

AIM:To investigate the association between nonalcoholic fatty liver disease(NAFLD) and liver cancer,and NAFLD prevalence in different liver tumors.METHODS:This is a retrospective study of the clinical,laboratory and histological data of 120 patients diagnosed with primary or secondary hepatic neoplasms and treated at a tertiary center where they underwent hepatic resection and/or liver transplantation,with subsequent evaluation of the explant or liver biopsy.The following criteria were used to exclude patients from the study:a history of alcohol abuse,hepatitis B or C infection,no tumor detected in the liver tissue examined by histological analysis,and the presence of chronic autoimmune hepatitis,hemochromatosis,Wilson’s disease,or hepatoblastoma.The occurrence of NAFLD and the association with its known risk factors were studied.The risk factors considered were diabetes mellitus,impaired glucose tolerance,impaired fasting glucose,body mass index,dyslipidemia,and arterial hypertension.Presence of reticulin fibers in the hepatic neoplasms was assessed by histological analysis using slide-mounted specimens stained with either hematoxylin and eosin or Masson’s trichrome and silver impregnation.Analysis of tumor-free liver parenchyma was carried out to determine the association between NAFLD and its histological grade.RESULTS:No difference was found in the association of NAFLD with the general population(34.2% and 30.0% respectively,95%CI:25.8-43.4).Evaluation by cancer type showed that NAFLD was more prevalent in patients with liver metastasis of colorectal cancer than in patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma(OR = 3.99,95%CI:1.78-8.94,P < 0.001 vs OR = 0.60,95%CI:0.18-2.01,P = 0.406 and OR = 0.70,95%CI:0.18-2.80,P = 0.613,respectively).There was a higher prevalence of liver fibrosis in patients with hepatocellular carcinoma(OR = 3.50,95%CI:1.06-11.57,P = 0.032).Evaluation of the relationship between the presence of NAFLD,nonalcoholic steatohepatitis,and liver fibrosis,and their risk factors,showed no significant statistical association for any of the tumors studied.CONCLUSION:NAFLD is more common in patients with liver metastases caused by colorectal cancer.     

Erythropoietic and hepatic porphyrias

Porphyrias are divided into erythropoietic and hepatic manifestations. Erythropoietic porphyrias are characterized by cutaneous symptoms and appear in early childhood. Erythropoietic protoporphyria is complicated by cholestatic liver cirrhosis and progressive hepatic failure in 10% of patients. Acute hepatic porphyrias (-aminolaevulinic acid dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria and variegate porphyria) are characterized by variable extrahepatic gastrointestinal, neurological–psychiatric and cardiovascular manifestations requiring early diagnosis to avoid life-threatening complications. Acute hepatic porphyrias are pharmacogenetic and molecular regulatory diseases (without porphyrin accumulation) mainly induced by drugs, sex hormones, fasting or alcohol. The disease process depends on the derepression of hepatic -aminolaevulinic acid synthase following haem depletion. In contrast to the acute porphyrias, nonacute, chronic hepatic porphyrias such as porphyria cutanea tarda are porphyrin accumulation disorders leading to cutaneous symptoms associated with liver disease, especially caused by alcohol or viral hepatitis. Alcohol, oestrogens, haemodialysis, hepatitis C and AIDS are triggering factors. Porphyria cutanea tarda is the most common porphyria, followed by acute intermittent porphyria and erythropoietic protoporphyria. The molecular genetics of the porphyrias is very heterogenous. Nearly every family has its own mutation. The mutations identified account for the corresponding enzymatic deficiencies, which may remain clinically silent throughout life. Thus, the recognition of the overt disorder with extrahepatic manifestations depends on the demonstration of biochemical abnormalities due to these primary defects and compensatory hepatic overexpression of hepatic -aminolaevulinic acid synthase in the acute porphyrias. Consequently, haem precursors are synthesized in excess. The increased metabolites upstream of the enzymatic defect are excreted into urine and faeces. The diagnosis is based on their evaluation. Primary enzymatic or molecular analyses are noncontributary and may be misleading. Acute polysymptomatic exacerbations accompany a high excretory constellation of porphyrin precursors -aminolaevulinic acid and porphobilinogen. Homozygous or compound heterozygous variants of acute hepatic porphyrias may already manifest in childhood.     

Hepatocellular carcinoma in the Rhodesian African

We have carried out a prospective survey of 28 primary liver carcinomas over one year. Hepatocellular carcinoma is the commonest malignancy seen in Rhodesian blacks, which results in a high index of suspicion and accounts for the 96.4% positive diagnosis before death in this study. The age distribution was evenly spread through adult life with no definite peak incidence. Some were young and without evidence of chronic liver disease, but many had the stigmata of established hepatic disease. This contrasts with the common assertion that in areas of high incidence for primary liver cancer those affected are mainly young and lack signs of chronic liver disease. The commonest presenting symptoms were abdominal pain and swelling and weight loss. Hepatomegaly, often tender and nodular, was present in all but one. The incidence of alpha-feto protein, 46.5%, is low compared with other countries where primary liver cancer is common. Hepatitis B antigen was absent in all 28, suggesting that there is no association between the persistence of the antigen and hepatocellular carcinoma in Rhodesia. Liver function tests, although abnormal, were never diagnostic of primary liver cancer. We have confirmed the association of high alcohol consumption and cirrhosis with hepatocellular carcinoma.