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Tumor immunotherapy, induce diabetes, stop the drug? Massachusetts General Hospital case

 Last Update: 2022-11-01
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A patient with metastatic melanoma was quickly diagnosed with diabetes
melaise after worsening fatigue, thirst, and nocturia during treatment.
After carefully identifying the various possible causes, doctors eventually target immune checkpoint inhibitors
.
How to balance tumor and diabetes treatment is a very difficult problem, and doctors at Massachusetts General Hospital give treatment countermeasures
.
The patient is currently with a stable tumor and has not been rehospitalized
for diabetes.

We will brief this case
here.
To read the full translation, please visit the NEJM Medical Frontiers official website, APP or click on the WeChat mini program picture
.

For more information, see NEJM Editor-in-Chief Forum: Rheumatic Immunology Frontier Research | Case Statement at 7 p.
m.
this Friday
A 68-year-old patient with metastatic melanoma is evaluated
at our cancer center for fatigue and weight loss.

Six years prior to this assessment, the patient was diagnosed with superficial diffuse melanoma
of the left shoulder.
He underwent extensive local excision; Sentinel lymph node biopsy shows no melanoma metastases
.
One year prior to this assessment, the patient began to experience slurred speech and weakness
in his left hand.
Imaging studies show a mass in the parietal lobe and a mass in the left hilus
.
Doctors perform craniotomy of brain tumors; The pathological examination of the excised specimen is consistent with melanoma, and the lung mass biopsy conclusion is consistent
.
After surgery, the patient developed convulsive seizures and began treatment with levetiracetam
.
This is followed by radiation therapy to the parietal lobectomy space and pembrolizumab
.

Four months before this evaluation, after 7 cycles of pembrolizumab treatment, the blood thyrotropin level was 9.
4 μIU/mL (reference range, 0.
4~5.
0), and the free thyroxine level was 12 pmol/L (reference range, 12~23 pmol/L); The patient is started with
levothyroxine.
Three months prior to this assessment, after 8 cycles of pembrolizumab therapy, the patient developed exertional angina, underwent a coronary catheter, and had 2 drug-eluting stents
placed.
After 1 month, treatment with pembrolizumab is continued
.

When the patient went to the cancer center as scheduled to receive pembrolizumab infusion, he reported a 3-week history of fatigue and 2 weeks of worsening thirst and nocturia, and the need to urinate up to three times
a night.
Although there was no change in appetite and eating habits, he lost 5 kg of weight in the past 3 weeks
.
No headache, no changes in
vision.

On examination, the body temperature was 36.
4°C, the heart rate was 75 beats per minute, the blood pressure was 128/66 mmHg, the respiratory rate was 18 breaths per minute, and the oxygen saturation was 100%
when the patient breathed ambient air.
The BMI was 29.
0
.
Cardiopulmonary examination showed no abnormalities
.
No leg edema
.
Muscle mass is normal, as is arm and leg strength
.
No rash, no bruising, no skin tone changes
.
Other histories include hyperlipidaemia, hypothyroidism, and coronary heart disease
.
Medications include aspirin, atorvastatin, clopidogrel, levetiracetam, levothyroxine, metoprolol, and pembrolizumab
.
The patient does not smoke, does not drink alcohol, does not use illegal drugs
.
The patient lives in the New England region of the United States and is a retired police officer
.
His father, sister and brother have melanoma
.
The patient has no family history of
diabetes.

Complete blood count, liver function tests, and serum thyrotropin levels are normal
.
The blood glucose level is 28.
03 mmol/L (reference range, 3.
89~6.
11 mmol/L).

Other laboratory findings are shown in Table 1
.

Table 1.
Laboratory test data
patients are sent to the emergency department
of our hospital.
Differential diagnosis
The 68-year-old patient with metastatic melanoma reported several weeks of fatigue, weight loss, polyuria, and polydipsia; Blood tests show significant hyperglycemia
.
The background of hyperglycemia includes ongoing cancer treatment and recent episodes of two diseases: hypothyroidism and symptomatic coronary heart disease
.
The patient's current range of symptoms can be attributed to hyperglycemia
.
He meets the criteria for new-onset diabetes issued by the American Diabetes Association, including hyperglycemia or typical symptoms of hyperglycemic crises, with a random blood glucose level of ≥ 11.
10 mmol/L
.

New-onset diabetes is useful
to review the homeostatic mechanism of glucose before the initial differential diagnosis of new-onset diabetes in this patient.
Blood sugar levels are mainly regulated
by insulin and glucagon.
Glucagon often works
synergistically with other counterregulatory hormones outside the pancreas, such as cortisol, epinephrine, and growth hormone.
Some hyperglycemias are caused by multiple mechanisms, and hyperglycemia in this patient may be caused
by insulin deficiency, insulin resistance, anti-regulatory hormone overdose, or a combination of these mechanisms.

Insulin deficiency

Insulin deficiency can be absolute deficiency (complete loss of the ability to produce insulin) or relative deficiency (insufficient insulin production relative to the body's needs).

Immune-mediated destruction of pancreatic β cells eventually leads to a complete loss of the ability to produce insulin, leading to type 1 diabetes
.
This can occur alone or as part of
autoimmune polyendocrine syndrome associated with other endocrine disorders such as adrenal insufficiency, thyroid disease, or hypogonadism.
Although hypothyroidism has recently been identified, its clinical features are inconsistent
with adrenal insufficiency caused by autoimmune polyendocrine glandular syndrome type II.

Other causes of β cell destruction and insulin deficiency include conditions that lead to overall pancreatic dysfunction, such as hemochromatosis, cystic fibrosis, chronic pancreatitis, or extensive pancreatectomy
.
However, the patient does not present with symptoms of exocrine pancreatic insufficiency, such as abdominal cramps or steatorrhea.

Defects in genes that regulate β cell function, insulin production, or insulin secretion can lead to clinical diabetes
.
These defective phenotypes and penetrance vary widely, but the patient's older age and no family history of diabetes make this unlikely
.

Insulin resistance

Insulin resistance is the body's inability to respond
adequately to the insulin it secretes.
Insulin resistance often occurs
as part of metabolic syndrome, along with obesity, hypertension, and dyslipidemia.
Over time, insulin resistance leads to β cell dysfunction and relative deficiency of insulin, manifested as hyperglycemia, leading to type 2 diabetes
.
The patient has hypertension, cardiovascular disease, a body mass index of 29.
0, and features of metabolic syndrome, so type 2 diabetes may explain his current symptoms
.
In rare cases, genetic mutations affecting insulin receptors or anti-insulin receptor autoantibodies lead to a functional insulin resistance state
.
These causes of insulin resistance are usually seen in middle-aged women with other autoimmune diseases, so these diagnoses are unlikely in this patient
.

Counter-regulatory hormone overdose

Glucagon, cortisol, epinephrine, and growth hormone are key hormones
for normal secretion as a protective mechanism against hypoglycemia for raising serum glucose levels.
Individually, each of these hormones may be produced inappropriately by hormone-secreting tumors or after the homeostatic feedback loop in the body has failed
.
The patient does not have the typical features of glucagonoma, Cushing's syndrome, pheochromocytoma, and acromegaly, so these primary endocrine disorders are unlikely to explain their presentation
.
Upregulation of these hormones can also occur in critical illness situations
.
Although the patient is critically ill, his symptoms can be attributed to hyperglycaemia; There is no convincing evidence that a previous condition causes hyperglycemia
.

Drug use

Certain medications can cause insulin deficiency, insulin resistance, or too much counterregulatory hormones, which can lead to high blood sugar
.
Glucocorticoids act similarly to endogenous cortisol and are a common cause of
hyperglycaemia.
The patient was not taking any glucocorticoids, but he was taking metoprolol and was also receiving pembrolizumab, a monoclonal antibody
against PD-1 expressed by T lymphocytes.

Pembrolizumab and other immune checkpoint inhibitors (ICIs) amplify the body's immune response, and a large number of adverse events can be attributed to ICI-induced autoimmune responses
.
These immune-related adverse events can affect almost every organ system and range in severity from mild to life-threatening
.
Among the endocrine diseases associated with ICI that have been reported, ICI-induced diabetes is very rare
.
When ICI-induced diabetes mellitus, patients usually have acute manifestations of ketoacidosis, low or undetectable C-peptide levels, and pancreatic autoantibodies
are detectable in about half of cases.
ICI-induced thyroid dysfunction is more common, and recent hypothyroidism may be associated with
pembrolizumab therapy.

The presence of ketone bodies in serum and urine and elevated serum anion gaps suggest ketoacid production
.
Ketone bodies
are produced when cells cannot use glucose and rely on free fatty acid metabolism.
This process may be associated with chronic alcoholism and severe malnutrition, in which glycogen stores are depleted, gluconeogenesis is impaired, and counterregulatory hormones are upregulated
.
However, the patient neither drank alcohol nor showed signs of
severe malnutrition.

The third cause of ketogenic action is an almost complete lack of insulin, a state that prevents cells from absorbing glucose
from the bloodstream.
In patients with autoimmune (type 1) diabetes, acute hyperglycaemia with ketosis is a common presenting symptom; Subsequently, β cells are destroyed leading to an absolute lack of
insulin.
In contrast, ketosis
is rare in patients with insulin resistance syndrome and relative insin deficiency.
It is important to note that although the patient had elevated anion gap and serum ketone levels, no acidemia
occurred.
However, venous blood gas analysis and serum bicarbonate levels consistent with bicarbonate excess, suggesting that concomitant metabolic alkalosis keeps serum pH within the normal range
.

This patient presents with acute symptoms of new-onset hyperglycemia and associated ketosis, with autoimmune diabetes being the primary diagnosis
.
The typical type 1 diabetes usually first develops in childhood or adolescence, and this patient develops symptoms
at age 68.
Pembrolizumab therapy was the most convincing risk factor for new-onset autoimmune diabetes in this patient; The suspected diagnosis is ICI-induced diabetes
.
There are no definitive diagnostic tests to confirm this diagnosis, but it would be helpful
to check blood levels of glycated hemoglobin, islet cell autoantibodies, and C-peptide levels after insulin therapy and stable blood glucose levels.

Clinical diagnosis of diabetes
induced by immune checkpoint inhibitors.

Diagnostic tests The patient's glycated hemoglobin level increased from 5.
7% to 11.
0%
within 3 months.
In the absence of risk factors for weight gain and pancreatic insufficiency, increased levels of glycated hemoglobin and rapid progression of diabetes strongly support the diagnosis
of autoimmune diabetes.
Autoantibody and endogenous insulin testing can help determine the major subtypes of diabetes (Figure 1).

The patient tests positive for serum and urine ketones, suggesting insulin deficiency
.
C-peptide levels are markers of endogenous insulin, but may be falsely low in the presence of chronic hyperglycaemia; Therefore, when diabetes is under control, patient C-peptide levels
are usually measured on an outpatient basis.
The next diagnostic test is to measure
the level of autoantibodies.
In this case, glutamate decarboxylase 65 (GAD65) and islet antigen 2 (IA-2) autoantibodies were negative, ruling out late-onset autoimmune diabetes
in adults.
In patients with ICI-induced diabetes, autoantibody tests may be positive or negative
.
ICI-induced diabetes is the most likely diagnosis
.

Figure 1 Diagnososes diabetic subtypes based on autoantibody testing and endogenous insulin production

Some subtypes
of diabetes are listed based on the presence of glutamate decarboxylase 65 (GAD65) or islet antigen 2 (IA-2) autoantibodies, and the presence of endogenous insulin production (β cellular function) based on C-peptide levels.
In patients with immune checkpoint inhibitor (ICI)-induced diabetes, autoantibody tests may be positive or negative
.

Laboratory diagnosis
of diabetes
induced by immune checkpoint inhibitors.

Treatment strategy discussion
Initial treatment

The first step in the patient's initial treatment is to determine whether he has diabetic ketoacidosis
.
Insulin deficiency and relative glucagon excess can lead to hyperglycemia in several ways, including decreased glucose uptake by insulin-sensitive tissues and increased
glucose output from the liver through gluconeogenesis and glycogenolysis.
Fat is then broken down and the free fatty acids released can be produced by the liver to ketones
.
As ketones accumulate, anionic gap metabolic acidosis develops, and some patients may experience a significant drop in
pH.
Treatment of diabetic ketoacidosis includes aggressive fluid resuscitation and electrolyte replacement to counteract osmotic diuresis
caused by hyperglycaemia.
Need for insulin therapy to stop ketone production; Although intravenous insulin has long been considered the treatment of choice, there is evidence to support subcutaneous insulin for mild or moderate diabetic ketoacidosis (pH > 7.
00).

The patient's initial laboratory findings show hyperglycaemia, ketosis, and anionic gap metabolic acidosis, findings consistent with diabetic ketoacidosis
.
Depending on the degree of acidosis, diabetic ketoacidosis is mild, moderate, or severe
.
If alkalosis is also present, the classification is difficult to determine, as is the case in this case (due to normal venous pH).

It is assumed that the patient has mild diabetic ketoacidosis and is treated with subcutaneous insulin
.

The second step in the initial treatment of this patient is to decide whether long-term insulin therapy
is needed.
Because ICI-induced diabetes is most likely the diagnosis, long-term insulin therapy
is expected.
In the emergency department, patients receive fluid resuscitation and start a basal
insulin + rapid-acting insulin given with meals.
Repeat examination after 12 hours showed a decrease in blood glucose levels to 7.
27 mmol/L, an increase in carbon dioxide levels to 22 mmol/L, and an anion gap decrease to 17 mmol/L
.
The patient was discharged home at the same time as receiving the insulin regimen and planned for follow-up with an endocrinologist
.

Long-term treatment

For long-term treatment of this patient, two points need to be considered: How should newly diagnosed diabetes be treated? Should pembrolizumab be continued?

Data to help make these decisions are limited, mainly because ICI-induced diabetes is rare
.
An early meta-analysis of 38 clinical trials showed that of 7,551 participants, only 13 – an incidence of 0.
2%.

Although subsequent retrospective analyses estimated a slightly higher incidence of ICI-induced diabetes, the total number of cases remained small
.
As a result, the understanding of ICI-induced heterogeneity in diabetes is still deepening
.
Therefore, long-term treatment requires careful consideration of the specific blood glucose profile
of each patient.

ICI-induced diabetes is caused by immune-mediated destruction of β cells, and the clinical manifestations are caused
by decreased insulin production.
Therefore, insulin
is required for treatment.
The earliest reported cases of ICI-induced diabetes occurred in patients with diabetic ketoacidosis and rapidly progressing diabetes, with negative endogenous insulin production and often positive
islet cell autoantibodies.
However, another retrospective study showed that only 4 out of 10 patients with ICI-induced diabetes developed diabetic ketoacidosis
.
This feature is more consistent with this patient's presentation
.
Although patients had mild diabetic ketoacidosis at the time of onset, C-peptide levels were normal 2 months after diagnosis, a finding that suggests that endogenous insulin production is still present
.

This may be due to a deeper understanding of ICI-induced diabetes that has led to an earlier diagnosis with less severe
clinical manifestations at the time of diagnosis.
As the use of ICI increases, so does the awareness of immune-related adverse events, including ICI-induced diabetes
.
ICI-induced diabetes can now be detected before symptoms or during periods of blood glucose abnormalities, whereas in the past, ICI-induced diabetes was only considered
in patients with fulminant symptoms.
If the disease is detected early in the blood glucose abnormalities, patients are expected to gradually lose β cell mass and endogenous insulin production
.

Previously unreported ICI-induced diabetes heterogeneity
may now be gradually observed.
There is some evidence in the described cases to prove this
.
Of the 27 ICI-induced diabetes patients identified between 2012 and 2018, 60% did not test positive
for islet cell autoantibodies.
Patients with and without autoantibodies may have different mechanisms and clinical courses
of immune damage.

Notably, heterogeneity
has been reported in an increasing number of patients with type 1 diabetes.
Heterogeneity of immune-related adverse events was more pronounced
in patients with ICI-induced thyroiditis.
Patients with ICI-induced thyroiditis may present with a variety of phenotypes, including transient hyperthyroidism followed by permanent or transient hypothyroidism, transient hyperthyroidism only, and permanent hypothyroidism only
.

The increasing number of ICI-induced case reports of diabetes has revealed the heterogeneity of the disease, and it may be appropriate to reconsider the basal preprandial insulin regimen
used in this patient.
If the destruction of islet cells is self-limited and there is sufficient pancreatic reserve, a simpler insulin regimen such as premixed insulin or basal insulin
only may be considered.
In this patient, the rationale for supporting basal preprandial insulin regimens outweighs the benefits
of simpler regimens.

A second consideration regarding the long-term treatment of this patient is whether or not
to continue pembrolizumab.
Because endocrine immune-related adverse events are defined in terms of loss of function rather than inflammation, we suspect that damage from pembrolizumab has occurred
at the time of diagnosis.
Therefore, permanent cessation of ICI therapy is unlikely to change the course of ICI-induced diabetes, and ICI therapy
can be continued once the patient is clinically stable.
This may be oversimplified; Patients with the disease detected early in the abnormal phase of blood glucose may have persistent immune-mediated disruption that can be slowed or stopped
with ICI discontinuation.
However, even in this case, ICI-induced diabetes can be controlled with insulin, so the development of this condition will not be a reason to
stop potentially life-saving cancer treatment.
Shortly after the patient was diagnosed with ICI-induced diabetes, aminotransferase levels were elevated, suggesting the possibility
of ICI-induced hepatitis.
Doctors stop pembrolizumab and plan to restart treatment
if the cancer returns.

The patient has been diagnosed with ICI-induced diabetes for 3 years
.
Its melanoma is currently stable and pembrolizumab treatment has not been restarted
.
While receiving basal preprandial insulin therapy, their blood glucose continued to be well controlled; Since his diagnosis, he has received a total of 44 stable doses
per day.
He has not been hospitalized for diabetes and has not developed any diabetes-related complications
.

Final diagnosis
of immune checkpoint inhibitor-induced diabetes
.

References

1.
Wing JR, Kimball A, Rengarajan M.
Case 6-2022: A 68-year-old man with fatigue, weight loss, and hyperglycemia.
N Engl J Med 2022; 386:781-7.

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