Influence Of Alcohol Use Disorder (AUD), Antiepileptic Drug (AED) And Previous Gastrectomy on Elevated Mean Corpuscular Volume (MCV)

Bando H, Kato Y, Yamashita H and Ogura K

Published on: 2025-07-13

Abstract

The case is 67-year-old male with alcohol use disorder (AUD) for long. As past history, he underwent the Billroth-II anastomosis for pylorus-proximal gastrectomy against gastric cancer at the age of 59. Furthermore, he was diagnosed with cerebral venous sinus thrombosis and symptomatic epilepsy. Then, he has been provided levetiracetam and edoxaban tosilate. For laboratory data, elevated gamma-glutamyltransferase (GGT) and mean corpuscular volume (MCV) and normal ranges of Vitamin B₁₂ and folate were observed. Medical problems included the relationships among alcohol intake, liver function, complete blood count (CBC), MCV, liver, pancreas, continuation of levetiracetam and edoxaban. Various perspectives were described.

Keywords

Alcohol use disorder (AUD); Gamma-glutamyltransferase (GGT); Mean corpuscular volume (MCV); Levetiracetam (LEV); Edoxaban tosilate hydrate

Introduction

Alcohol use disorder (AUD) and excessive alcohol drinking have been public health concerns [1]. Such situation contributes to various negative psychosocial, medical and economic consequences across the world [2]. Adequate use of several biomarkers for alcohol drinking and applications of AUD for clinical trials can be discussed for various reports [3]. Clinical practice and research using such biomarkers will increase the perspectives and accuracy of the data and may bring targeted strategies for diagnosis, prevention, therapy of excessive alcohol use [4].

Habitual alcohol drinking is known to have association with influence to diabetes, liver disease, hemoglobin (Hb) and mean corpuscular volume (MCV). Relationship with alcohol consumption and complete blood count (CBC) was studied [5]. As a result, mean Hb and MCV showed significant high values in regular alcohol consumers. Furthermore, both GGT and HDL-C tended to be higher as frequent drinking situation. It has been well known situation that MCV may increase with excessive drinking. The probable period necessary for increased MCV to return to normal range would be about 2-4 months [6]. This is longer than the case of GGT. The related mechanism of increasing MCV by habitual drinking seemed to be the changes in red blood cell (RBC). In detail, the lipid composition of RBC membrane may be involved in the influence by the direct action of ethanol, where the involvement of acetaldehyde may be also crucial for this mechanism.

On the other hand, it is known that an increase in MCV is observed in the case of administration of antiepileptic drug (AED). In clinical practice, valproic acid (VPA), levetiracetam (LEV), oxcarbazepine (OXC), phenobarbital (PB), carbamazepine (CBZ), etc. have been common for the younger generation [7]. For adult and traumatic cases, clinical research has been progressing concerning several agents, including LEV, phenytoin and CBZ [8]. Among these, LEV has been shown to be a broad-spectrum AED with a low incidence of cognitive impairment. Since it is not metabolized in the liver, it has the advantage of having fewer side effects than phenytoin and CBZ.

As mentioned above, both alcohol intake and AED are involved in the rise in MCV. We recently encountered a patient with high MCV and also both causes. As our clinical practice, we have been treating lifestyle-related diseases, atherosclerotic cardiovascular disease (ASCVD), diabetes, chronic kidney disease (CKD), and general primary care medicine, and have published various reports for years [9,10]. We conducted a detailed study of this case with related perspectives, which we report in this article.

Case Presentation

The patient is a 67-year-old man. In 2017 (at age 59), he underwent surgery for gastric cancer with a Bi-II (Billroth-II) anastomosis for pylorus-proximal gastrectomy. He was followed up every six months for five years, but no particular changes were observed until 2022. In 2018, he developed headache and behavioral abnormality, and was diagnosed with cerebral venous sinus thrombosis and symptomatic epilepsy. He has since been taking levetiracetam 1000 mg/day and edoxaban tosilate hydrate 30 mg/day.

Since the spring of 2025, the patient developed chest and abdominal discomfort. Regarding recent lifestyle habits, the patient drinks 4 glasses (Japanese sake 180 cc x 4 = 720cc) of alcohol per day, with no days off. Vital signs are blood pressure 169/100 mmHg, P88 /min, SpO₂ 99%. There are no significant changes in consciousness, conversation, chest, abdominal, or neurological findings. The results of the blood test are shown in Table 1. Among them, GGT and MCV showed elevated values as 110 fL. Blood concentration showed normal range values of Vitamin B₁₂ 194 pg/mL (180-914) and folate 16.2 ng/mL (4<).

An abdominal CT scan was performed, and fatty liver and pancreatic cysts were found, but no abnormalities were found in the gallbladder, kidneys, spleen, or other organs (Figure 1).

Table 1: Progress of Biochemistry.

			2021	2023	2024	2025
		Units	April	April	June	June
Liver
	AST	(U/L)	40	60	36	44
	ALT	(U/L)	15	11	15	15
	GGT	(U/L)	-	72	63	104
Renal
	UA	(mg/dL)	-	6.6	6.6	6.2
	BUN	(mg/dL)	15	-	14	12
	Cre	(mg/dL)	0.78	0.71	0.75	0.71
	Na	(mEq/L)	139	143	143
	Cl	(mEq/L)	103	103	103
	K	(mEq/L)	5.3	5.2	5.1
	Ca	(mg/dL)			9.0
Lipids
	HDL	(mg/dL)			86	101
	LDL	(mg/dL)			73	80
	TG	(mg/dL)			42	91
Diabetes
	glucose	(mg/dL)	73			75
	HbA1c	(%)	-			5.3
CBC
	WBC	(x10*2/μL)	23	18	25	30
	RBC	(x10*4/μL)	331	345	338	369
	Hb	(g/dL)	13.1	12.8	12.4	13.7
	Ht	(%)	37.3	38.3	39.6	41.3
	MCV	(fL)	112.7	111	117.2	111.9
	MCH	(pg)	39.6	37.1	36.7	37.1
	MCHC	(%)	35.1	33.4	31.3	33.2
	PLT	(x10*4/μL)	22.5	24.2	28.9	23.1

Figure 1: Results of abdominal CT scan. a. Fatty liver was observed. b. Pancreatic cyst was found.

Medical Problems and Progress

From the above, the following medical problems were found.

#1: Current case is a 67-year-old male.

#2: excessive alcohol consumption as AUD for years

#3: GGT are elevated, and the ratio of AST>ALT is high, suggesting a decline in liver function

#4: Abdominal CT scan suggests fatty liver and pancreatic cyst. TP, Alb, and platelet were within normal range.

#5: At the age of 59, he was diagnosed with gastric cancer and underwent gastrectomy with Billroth II anastomosis. After that, he has not continued particular eating habits.

#6: Macrocytic anemia: MCV showed high values of 110 fL. Vitamin B₁₂and folate concentrations are within normal range.

#7: The case has cerebral venous sinus thrombosis, symptomatic epilepsy, taking levetiracetam and edoxaban.

Certain relationships were found among these medical problems.

#1 and #2: It shows that alcohol intake has continued since a young age, and no apparent relationship seems to be present to the gastric cancer, gastric surgery, cerebral venous sinus thrombosis, and symptomatic epilepsy at the age of 59-60.

#3 and 4: The extremely high GGT and large AST/ALT ratio suggested the possibility of liver cirrhosis. However, the abdominal CT images of the liver and the results of TP, albumin and platelet did not suggest that the liver had reached the level of cirrhosis. The patient had fatty liver, suggesting the presence of alcoholic hepatitis. The involvement of hepatitis B and C viruses has been ruled out in the past. The relationship of the pancreatic cyst to alcohol is unclear.

#5 and 6: At the age of 59, the patient was diagnosed with gastric cancer and underwent surgery for gastrectomy with Billroth II anastomosis. As for the clinical course, the patient did not show abnormal eating habit. The macrocytic anemia might be possibly related to the gastrectomy.

#6 and 7: The patient had headaches and behavioral abnormalities, and was diagnosed with cerebral venous sinus thrombosis and symptomatic epilepsy. Since then, the patient has been taking levetiracetam 1000 mg/day and edoxaban tosilate hydrate 30 mg/day, and there is a possibility that the medications may be causing macrocytic anemia.

Ethical Standards

This case was complied with the guideline of Declaration in Helsinki [11]. The principle is evaluated by ethical regulation. The guideline was from Ministry of Education, Culture, Sports, Science Technology and Ministry of Health, Labor and Welfare in Japan. Authors had set up ethical committee in the hospital, with the director, doctors, head nurse, pharmacist, dietitian, and legal professional. Our staffs had discussed for the protocol and agreed them. Informed consent was obtained from the patient by the document.

Discussion

The characteristic point of this case would be elevated value of MCV.?Concerning this situation, three possible reasons would be present about the abnormality of red blood cell (RBC). They are i) the long-term continuation of excessive consumption of alcohol intake, ii) the long-term use of levetiracetam as an AED, and iii) previous history of the gastrectomy due to gastric cancer. Several perspectives will be described in this order.

Across the world, one of the most important global and public health would be AUD issue [12]. From illness burden point of view, alcohol is the third leading cause of death. Recent study showed a cross-sectional observational study, in which 25 moderate alcoholics, 25 severe alcoholics, and 50 adult non-alcoholics received the research [13]. As a result, anemia was found in 725 of moderate drinkers and 76% of severe alcoholics. The value of MCV > 99 fL was observed in 8%/28% of moderate/heavy drinkers. Furthermore, alcoholics showed some abnormal morphology of red blood cell (RBC), such as ovalocytes, elliptocytes, acanthocytes, stomatocytes and target cells [14].

Epilepsy has been one of the most common neurological disorder during childhood. Long-term effects of LEV (n=49) and valproic acid (VPA) (n=14) were investigated for baseline and 24 month [15]. In the case of LEV, significant increases were found for MCV (p=0.006), and mean corpuscular hemoglobin (MCH) (p=0.004). Similarly, VPA showed significant increased values in MCV and monocyte % as p=0.022 and p=0.01, respectively. LEV has been a broad-spectrum AED which is widely provided. The enrolled patients were pediatric cases (n=64) receiving LEV as AED monotherapy. When comparing the blood data between baseline and 12-month later, hematocrit, hemoglobin, MCV, and mean platelet volume increased, while white blood cell, platelet, neutrophil, and monocyte counts decreased (p<0.05) [16].

Among AEDs, VPA has been common agent for pediatric age group. Hematological side effects indicate anemia, thrombocytopenia, red cell aplasia and others [17]. A case showed anemia as Hb 1.9 g/dL, MCV 80 fL, MCH 27.1 pg, WBC 8200 /L, platelet 608,000/L, where discontinue of VPA will result in Hb 13 g/dL with improvement of anemia only for 1 month. A female child case showed early-onset seizures. Detail analysis detected the exome sequencing for a de novo heterozygous variant of TMEM63B. She received the combination treatments of ketogenic diet (KD) therapy and perampanel (PER) [18]. She showed macrocytic anemia and stable clinical progress by the combined therapy. PER is a noncompetitive AMPA-type glutamate receptor antagonist developed by Eisai, and was approved for manufacture and sale in Japan in 2016 as an AED. AMPA stands for α-amino-3-hydro-5-methyl-4-isoxazolepropionic acid.

From historical point of view, the relationship among gastrectomy, macrocytic anemia and Castle’s intrinsic factor has been known [19].?Large study was held concerning the vit B₁₂deficiency and post-gastrectomy [20]. The protocol was the review (n=645) for cases with gastric cancer who received total gastrectomy (TG, n = 176) vs distal subtotal gastrectomy (DG; n = 469) for 8 years. The cumulative vitamin B₁₂ deficiency rates were 100% for TG and 15.7% for DG after 4 years of surgery (p<0.001). Consequently, VitB₁₂ deficiency seems to show inevitable phenomenon and rather early metabolic sequela after TG. Thus, careful follow-up for anemia would be required for patients with gastrectomy.

Previous study showed the analyses of 161 cases with gastrectomy with follow up 4 years. Lots of cases were iron-deficiency anemia, and normocytic or macrocytic anemia were rarely found [21]. From the comparison with female/male ratio for anemia, significantly more cases were observed in female cases. As a result, the incidents showed 35.4% vs 13.3% for 6 months, 60.4% vs 20.9% for 24 months and 66.7% vs 34.7% for 48 months, respectively. In the latest report, patients with upper gastrointestinal (UGI) cancer were investigated by the review of 26 papers for 15 years [22]. Among them, iron and vitamin B₁₂ were the most recommended micronutrients for three groups, which included UGI, esophageal and pancreatic cancer survivors. Consequently, long-term UGI cancer survivors would have at risk of micronutrient deficiency after surgery. A standardized approach to prevent, monitor, and treat micronutrient deficiencies is needed.

Certain limitation may be found in this article. Current case showed AUD that led to macrocytic anemia and also other health and medical problems. On the other hand, other probable factors can be involved in alcoholic metabolism and related pathophysiology. Consequently, this case would be followed up with attention.

In summary, 67-year-old male revealed some problems with alcoholism, macrocytic anemia, and other metabolic matters. Current impressive report will become hopefully useful perspectives for medical research and clinical practice in the future.

Conflict of interest: The authors declare no conflict of interest.

Funding: There was no funding received for this paper.

Journal of Biomedical Science and Research