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Journal of Medical Cases

Case Report

Volume 14, Number 6, June 2023, pages 185-190

Unique Variant of Zieve Syndrome With a Normal Reticulocyte Count

The triad of hyperlipidemia, hemolytic anemia, and jaundice in the setting of chronic alcohol abuse and liver damage compose Zieve syndrome [1]. This constellation of clinical findings was first described by Leslie Zieve in 1957 [2]. It is estimated that this syndrome is seen in approximately 1 in 1,600 hospital admissions [3]. The exact pathogenesis remains elusive, and our current knowledge remains confined to multiple hypotheses. Identification of Zieve syndrome is essential to provide timely treatment and high-value care without subjecting the patient to unnecessary testing in the search for a diagnosis.

The syndrome is slowly gaining recognition in the literature, and as a result, the clinical significance is not well understood. We present a rare case of Zieve syndrome with the unusual finding of a normal reticulocyte count to bring further awareness of this diagnosis, with an emphasis on the pathogenesis, presenting symptoms and labs, prognosis, and clinical management. We explain why an unconventional treatment strategy might prove beneficial in this unique variant. Additionally, we reviewed the literature for cases of Zieve syndrome dating back to 1958 to better characterize the clinical presentation and overall survival rates of this condition.

A 44-year-old female with a past medical history significant for hypothyroidism and alcohol use disorder, presented with a complaint of jaundice for the last 10 days. She also reported a 2-month history of weakness and lethargy. A targeted review of the systems was found to be negative. She reported a history of drinking three to four glasses of hard liquor every night for many years. Her only medication was 50 µg of levothyroxine. In the emergency department, the patient had tachycardia of 103 beats per minute with all other vitals within normal limits. Physical exam was significant for mild tachycardia, scleral icterus, jaundice, and mild abdominal distension with no fluid shift noted. She reported no family history of autoimmune disorders or liver disease, no recent blood transfusions, and no other over the counter medications or herbal supplements.

Initial laboratory values on admission are shown in Table 1.

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Table 1. Initial Laboratory Values on Admission

Other workup included a blood alcohol level of 0.306% (reference range < 0.005%), negative beta human chorionic gonadotropin hormone, normal ceruloplasmin levels and normal hepatitis panel. Peripheral blood smear showed mild anemia, mild thrombocytopenia, along with slight anisocytosis, slight macrocytes, moderate target cells. Direct Coomb’s showed a negative elution test and hence it was not considered significant by the lab. The anemia was hemolytic and non-immune in origin. Thus, laboratory findings were consistent with Zieve syndrome. Hemoglobin continued to downtrend during the patient’s hospital stay (Table 2).

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Table 2. Follow-Up Hemoglobin Values

Due to downtrending hemoglobin, gastroenterology was consulted. Additionally, a psychiatry consult was placed for assistance with alcohol cessation. The patient was started on appropriate therapy with furosemide and spironolactone, along with lactulose. She was monitored for alcohol withdrawal and counseled extensively on alcohol cessation. She was also recommended for an outpatient esophagogastroduodenoscopy to evaluate for varices. Discriminant function [4] was noted to be elevated at 47 so she was started on a 1-month course of prednisolone daily. Her condition improved and she was discharged with advice to follow-up with both gastroenterology and psychiatry as an outpatient.

At a follow-up visit 1 month later, the patient abstained from alcohol and completed the prescribed steroid course. Repeat labs (Table 3) at this time showed improvement in all three cell lines and a decrease in the total bilirubin suggesting resolution of hemolysis.

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Table 3. Follow-Up Laboratory Values 1 Month Later

Chronic alcohol use predisposes individuals to a wide range of adverse medical conditions such as macrocytic anemia, alcoholic hepatitis, and cirrhosis [5]. The goal of our case is to bring awareness to a rarely documented and an underrecognized complication of alcohol abuse known as Zieve syndrome. This disease process was first described by Dr. Leslie Zieve in 1958 and is composed of a specific constellation of clinical and laboratory findings which includes hyperlipidemia, hemolytic anemia, and jaundice [2]. The pathophysiology of Zieve syndrome remains poorly defined, but multiple theories have been proposed. It is suspected that the hemolysis seen in these patients results primarily from a profound elevation in triglycerides. The altered synthesis of lipoproteins, cholesterol, and fatty acids may induce hemolysis via instability of the erythrocyte membrane [6]. Recent studies now suggest that both toxic metabolites from ethanol and alcohol-induced vitamin E deficiency may also compound the red blood cell destruction through impaired functioning of crucial metabolic enzymes [7, 8]. The multifactorial mechanism for red blood cell destruction directly results in hemolytic anemia, contributing also to an elevation in unconjugated bilirubin levels. Often the hyperbilirubinemia that is seen is substantial as concurrent alcohol-mediated hepatocellular toxicity induces chronic cholestatic injury [9].

Clinicians should have a high degree of clinical suspicion for Zieve syndrome in individuals with a known history of excessive alcohol use who present with hemolytic normocytic anemia and hyperbilirubinemia, especially when subsequent workup is negative for gastrointestinal bleeding. The hemolytic nature of anemia can aid as a useful diagnostic tool to differentiate Zieve syndrome from isolated cases of alcohol dependence which often involves macrocytic anemia [10]. While Zieve syndrome typically can be identified by the classic triad, additional clinical findings may aid in the diagnosis. For example, abdominal pain was a universal finding seen in all 20 patients that Leslie Zieve studied [2]. Additional nonspecific symptoms that have been reported in the literature include fatigue, fever, nausea, and vomiting [11]. Given the hemolytic nature of anemia, labs generally reveal elevated reticulocyte count, increased lactate dehydrogenase (LDH), and decreased haptoglobin, with elevations in direct bilirubin and alkaline phosphatase. Coomb’s test is also negative [12]. The clinical importance of recognizing this syndrome comes from the fact that most patients rapidly recover within weeks of alcohol cessation [13]. Following alcohol abstinence, there is an intracellular shift of lipids from the plasma to adipose tissue in hepatocytes, thus eliminating the hypertriglyceridemia which is a suspected inciting trigger for the development and propagation of this unique syndrome [12].

The excessive alcohol consumption that is seen in this specific patient demographic can have toxic effects on the bone marrow as well. Suppression of hematopoietic stem cells results in impaired production of all three major cell lines, leading to decreased production of white blood cells, red blood cells, and platelets [14, 15]. It is possible that the bone marrow suppression induced by chronic alcohol use in our patient was insufficient to mount a proper response to the hemolytic environment in our patient. The most effective treatment for Zieve syndrome continues to be complete abstinence from alcohol [16]. Unconventional therapies such as plasmapheresis in a patient with massive elevations in triglyceride have also been reported [17]. It is believed that the commonly used scoring system of Maddrey discriminant function, which screens alcoholic patients who benefit from steroids, is ineffective in Zieve syndrome due to the temporary elevations in bilirubin levels that normalize after alcohol cessation [18]. In fact, the recommendation is to avoid corticosteroids entirely due to a lack of any proven efficacy [19]. While this may be true for patients with Zieve syndrome that have functional marrow, our patient was seen to benefit from both alcohol cessation in addition to steroids. We believe this to be due to the effect of steroids to stimulate the release of cells from the bone marrow, which has been proven in prior studies [20]. Our success mirrors that of other conditions such as hereditary spherocytosis, where corticosteroids can result in appropriate elevation in reticulocyte count with subsequent improvement in hemoglobin [21].

To date, there is a substantial gap in knowledge regarding the clinical presentation and overall prognosis of patients affected by Zieve syndrome. Following the initial pronouncement of this syndrome by Leslie Zieve in 1958, there have been over 100 documented cases in the literature. The only aggregate analysis of these case reports that we identified was by Liu et al in 2017, with a brief review focusing on the time period, country of origin, and subtype of each publication [22]. As a result, we aimed to conduct a more thorough review of documented case reports of Zieve syndrome with an emphasis on clinical presentation, lab values, and treatment outcomes while also including any additional cases that were published after 2017. After an extensive PubMed literature review of all case reports dating back to 1958 using the search term “Zieve syndrome”, we identified 31 documented cases [1, 3, 8, 11, 16, 17, 19, 22-31]. Inclusion criteria included: publications dated after Leslie Zieve’s original manuscript and cases that met all three components of the clinical triad including hyperlipidemia, hemolytic anemia, and jaundice. Exclusion criteria included: articles that were not open access or written in English text.

We document and summarize our findings below (Table 4 [1, 3, 8, 11, 16, 17, 19, 22-31], and Table 5, respectively). Overall, patients that met the triad for Zieve syndrome were on average 42.2 years of age with 54.8% being male. While abdominal pain was reported in nearly all of Zieve’s original 20 patients and has historically been considered a classic associated feature of this syndrome, our analysis demonstrates that this complaint is seen in just slightly over half of patients. Over the 31 patients we collected data on, the average initial triglyceride level was significantly elevated at 822.5 mg/dL. A majority of patients were anemic with an average hemoglobin of 8.2 g/dL and all patients reported so far had an elevated reticulocyte count. Overall, we demonstrate that Zieve syndrome carries a favorable prognosis, with 93.5% [29, 31] of individuals being successfully discharged and only two patients experiencing inpatient mortality.

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Table 4. Literature Review Findings

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Table 5. Summary of Table 4 Findings

It is important to recognize the typical findings that characterize Zieve syndrome since this diagnosis is relatively unknown. A high index of clinical suspicion is warranted in patients with alcohol use disorder who present with hemolytic anemia and jaundice. Additionally, a special emphasis should be placed on studying rare variants, such as our patient with a normal reticulocyte count, as they might help uncover undiscovered mechanisms at play. Ultimately, while our data suggest that this condition carries a favorable prognosis with timely identification and treatment interventions, further research regarding the pathophysiology of this syndrome is needed to better target future treatment strategies.

Our case aims to bring further awareness to the rare combination of clinical features, along with the complex pathophysiology, which underlies Zieve syndrome. Additionally, we present a unique subtype of Zieve syndrome with bone marrow suppression as demonstrated by a paradoxically low reticulocyte count which benefited from the use of corticosteroids. Following an extensive review of the literature, it is evident that Zieve syndrome can be promptly identified by the classical triad of clinical features on presentation including hyperlipidemia, hemolytic anemia, and jaundice. Additionally, abdominal pain may not be as reliable of a clinical finding as once previously thought. We demonstrate that appropriate intervention, primarily alcohol cessation, can result in promising recovery for these patients. Ultimately, we hope that our contribution to the knowledge of Zieve syndrome may lead to improved patient outcomes and a more robust treatment protocol in the future. We also hope to increase recognition of this rare variant of Zieve syndrome.

Acknowledgments

None to declare.

Financial Disclosure

None to declare.

Conflict of Interest

None to declare.

Informed Consent

Informed consent was taken from the patient before writing this case.

Author Contributions

Each author was individually involved in and made substantial contributions to conceptions and designs, acquisition of data, analysis, interpretation of data, drafting, and editing the manuscript. AV and SI contributed to the designs, acquisition of data, analysis, interpretation of data, drafting, and editing of the manuscript. HS and RP contributed to the drafting and editing of the manuscript. ST contributed to the designs and analysis of the manuscript. MH contributed to the designs, analysis, interpretation of data, and editing of the manuscript.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

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